Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma
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Cristina Trejo-Solís
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Norma Serrano-García
Abstract
Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival.
1 Introduction
The glioblastoma (GBM) is the most frequent and aggressive tumor of the central nervous system (CNS). The survival of patients with GBM is less than 2 years after diagnosis despite current therapies such as surgery, radiotherapy, chemotherapy, and immunotherapy (Mischel and Cloughesy 2003). GBM is characterized by cellular proliferation, mitosis, necrosis, and angiogenesis as well as high metabolism, which supports the malignity of this tumor (DeAngelis 2001; Grobben et al. 2002).
The alterations in GBM metabolism are related to several genetic modifications, including the down-regulation of tumor suppressors such as PTEN, NF-1, TSC1/2, p53, RB, fumarate hydratase (FH) (Costa et al. 2010), succinate dehydrogenase (SDH) (Dalla Pozza et al. 2020), as well as the up-regulation of oncogenes like MET (Costa et al. 2010), Ha/N-ras, WNT1 inducible signaling pathway protein 1 (WASP1) (Jing et al. 2017), v-SRC (Ahluwalia et al. 2010), or immune-responsive gene 1 (IRG1) (Pan et al. 2014). These modifications promote the overactivation of RTKs/RAS/PI3K/AKT/mTOR and RTKs/RAS/RAF/MEK/ERK signaling pathways, which modulate transcriptional factors including p53, c-myc, and HIF1, main regulators of cell metabolism. In addition, mutations in genes encoding enzymes and proteins from the TCA cycle and OXPHOS, respectively, promote the production of onco-metabolites and mitochondrial damage responsible for GBM pathogenesis (Gasmi et al. 2021).
GBM cells show an enhancing glycolytic phenotype (Warburg effect) due to the overexpression of most enzymes participating in the glycolytic pathway (Trejo-Solis et al. 2023). Glucose is metabolized to pyruvate, which is converted to lactate under aerobic conditions or can be oxidized via the TCA cycle. The transformation of glucose to pyruvate generates low amounts of energy (2ATP) but is important for biomass production, necessary for cell growth. Glucose-6-phosphate (G6P), a metabolite of glycolysis, is shunted to the pentose phosphate pathway for the formation of nucleotides and NADPH, necessary for glutathione (GSH) and lipid synthesis. Furthermore, dihydroxyacetone phosphate (DHAP) and 3-phosphoglycerate (3PG) are precursors of triacylglycerol as well as serine (Ser) and ceramide, respectively (Trejo-Solis et al. 2023).
Pyruvate can be translocated into mitochondria by the mitochondrial pyruvate carrier (MPC) to be transformed to acetyl-CoA and CO2 by the pyruvate dehydrogenase (PDH) complex and NADH (Nelson et al. 2017), thereby linking glycolysis and the Krebs cycle. On the other hand, pyruvate dehydrogenase kinase (PDHK) negatively regulates PDH activity, decreasing the oxidation of pyruvate in mitochondria and increasing the conversion of pyruvate to lactate and ethanol (Jha and Suk 2013).
Furthermore, pyruvate in the cytosol can be switched for malate (ML) or alanine (Ala) by reversible reactions catalyzed by malic enzyme 1 (ME1) or glutamate pyruvate transaminase 1 (GPT1), respectively (Corbet and Feron 2017). In addition, mitochondrial pyruvate can be metabolized to oxaloacetate (OA) via pyruvate decarboxylase (PD) or to alanine and αKG by GTP2, whereas α-ketoglutarate (αKG) can then be converted to malate and ultimately to OA in the TCA cycle (Wiese et al. 2021).
In this review, we focus on the canonical and non-canonical functions of enzymes, metabolites, and complexes from the TCA cycle and OXPHOS in GBM cells. Both metabolic pathways are essential for proliferation, survival, growth, angiogenesis, and invasion in GBM through anabolic, catabolic, and signaling functions for metabolites (Lu and Hunter 2018; Xu et al. 2021). Understanding these metabolic alterations is crucial for enhancing the development of novel therapeutic strategies for glioblastoma. Furthermore, we describe experimental drugs that block metabolism in glioblastoma treatment.
2 The tricarboxylic acid cycle (TCA) or Krebs cycle (KC)
The Krebs cycle (KC) or tricarboxylic acid cycle (TCA) is a core pathway for the metabolism of carbohydrates, lipids, and amino acids, and it is a fundamental part of oxidative phosphorylation. The TCA consists of eight enzymes located principally in the mitochondrial matrix, except for succinate dehydrogenase, localized in the mitochondrial inner membrane (SDH) (Figure 1) (Nelson et al. 2017). In the TCA cycle, there are three irreversible steps: the reactions catalyzed by citrate synthase (CS), isocitrate dehydrogenase (IDH), and α-ketoglutarate dehydrogenase (α-KGDH) (Nelson et al. 2017). The TCA cycle is mainly regulated by product feedback inhibition and substrate availability (Williamson and Cooper 1980). All the regulatory enzymes of the TCA, including PDH, are allosterically inhibited by NADH (Jha and Suk 2013). CS activity is regulated directly by accessible pools of either of its two substrates, oxaloacetate and acetyl-CoA (Williamson and Cooper 1980). IDH is considered one of the rate-limiting steps of the TCA cycle and is allosterically activated by ADP and inhibited by NADH. The α-KGDH is inhibited by its products, NADH and succinyl CoA, and may also be inhibited by GTP (Williamson and Cooper 1980).
Citrate synthase (CS) condenses Acetyl-CoA (Ac-CoA) with oxaloacetate (OA) to form citrate (CIT). CIT then translocates to the cytosol and becomes a target of ATP citrate lyase (ACL) and isocitrate dehydrogenase (IDH1), generating Ac-CoA, OA, and α-ketoglutarate (αKG), respectively. Furthermore, CIT induces apoptosis and inhibits phosphofructokinase 1 and 2 (PFK1, PFK2), insulin-like growth factor receptor (IGFR), and phosphoinositide 3-kinase (PI3K). Additionally, CIT is converted to cis-aconitate, which is further converted to isocitrate (ICIT) by aconitase (AC). The cis-aconitate is transformed into itaconate (IC) by immune-responsive gene 1 (IRG1), which inhibits aldolase (Aldo), glyceraldehyde-3-phosphate dehydrogenase (GA3PDH), pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and kelch-like ECH-associated protein 1 (Keap 1), as well as the generation of reactive oxygen species (ROS). ICIT is then converted to αKG by isocitrate dehydrogenase 1 and 2 (IDH1, IDH2). αKG activates prolyl hydroxylase domain-containing enzymes (PHD) and glutathione peroxidase (Gpx), and inactivates Jumonji C-domain containing histone demethylases (JMJDs) and 10–11 translocation (TETs), complex IV and V (C-IV, C–V), as well as generation of reactive oxygen species (ROS). On the other hand, IDHmut transforms αKG to 2-hydroxyglutarate (2HG), which inhibits TETs, JMJDs, and PDHs. Additionally, α-ketoglutarate dehydrogenase (α-KGDH) enzyme converts αKG to succinyl-CoA (Su-CoA), a precursor for Ac-CoA and heme synthesis. Su-CoA induces protein succinylation, such as pyruvate kinase isoform M2 (PKM2), and αKG is catalyzed to succinate (SCN) by succinyl CoA synthetase (SCS). SCN inhibits PDHK, JMJDs, TETs, and PHD2. Furthermore, SCN activates the SUCNR1/PI3K/AKT/HIF-1 signaling pathway in tumor-associated macrophages (TAMs) and, through autocrine signaling, induces the activation of ERK, cyclooxygenase-2 (COX-2), and endothelial nitric oxide synthase (eNOS) in glioma cells. SCN is then converted to fumarate (FM) by succinate dehydrogenase (SDH). FM inhibits PHD2, JMJDs, TETs, and complex I and II (C–I, C-II) of the electron transport chain (ETC). Furthermore, FM inhibits aconitase 2 and Keap1 by succination and is converted to malate (ML) by fumarase (FH). ML is then converted to pyruvate (pyr) via malic enzymes 1 and 2 (ME1, ME2). Additionally, ML is transformed to OA by malate dehydrogenase 2 (MDH1, MDH2). OA inhibits hexokinase 2, PFK1, lactate dehydrogenase (LDH), PKM2, PDH, AKT, and PHD2. Furthermore, OA is transformed to phosphoenolpyruvate (PEP) via phosphoenolpyruvate carboxykinase 1 (PEPCK1). OA is also a precursor of aspartate, which is converted to OA in the cytoplasm by glutamic-oxaloacetic transaminase 1 and 2 (GOT1, GOT2). Abbreviations: succinyl-CoA:3-ketoacid CoA transferase (SCOT), nitric oxide (NO), prostaglandin E2 (PGE2), glucose-6-phosphate (G6P), glucose-6-phosphate isomerase (G6PI), fructose-6-phosphate (F6P), phosphofructokinase 1 and 2 (PFK1, PFK2), fructose-1,6-biphosphate (F1,6BP), aldolase (Aldo), dihydroxyacetone phosphate (DHAP), glyceraldehyde-3-phosphate (GA3P), glyceraldehyde-3-phosphate dehydrogenase (GA3PDH), 1,3-bisphosphoglycerate (1,3BPG), 5′-adenosine monophosphate-activated protein kinase (AMPK), nicotinamide adenine dinucleotide phosphate (NADPH), and citrate lyase gene expression (ACL). Figure was created with BioRender.
There are five complexes involved in mitochondrial respiration and ATP synthesis: complex I (C–I) or NADH dehydrogenase, complex II (C-II) or succinate dehydrogenase, complex III (C-III) or ubiquinol-cytochrome c reductase, complex IV (C-IV) or cytochrome c oxidase (COX), and complex V (C–V) or ATP synthase. These complexes transfer electrons from nicotinamide adenine dinucleotide (NADH) or succinate to the Q coenzyme (ubiquinone) through complex I or II; then, this coenzyme passes electrons to C-III and the cytochrome c (Cyt C) accepts electron pairs, which are then transported to C-IV, and finally the electrons are transferred to oxygen (O2) generating water. The protons pumped into the intermembrane space by complex I, III, and IV create a proton gradient, which is the force that drives ATP synthesis by ATP synthase. Additionally, the dihydroorotate dehydrogenase (DHODH) enzyme transfers electrons to the ETC via ubiquinone through oxidation of dihydroorotate (DHO) to orotate. Also, proline, via proline dehydrogenase (PRODH), donates electrons to the ETC via FADH2. Furthermore, PRODH produces Δ1-pyrroline-5-carboxylate (P5C), which is converted to glutamate via P5C dehydrogenase. Glutamate is metabolized to αKG via glutamate dehydrogenase (GDH). Additionally, the ETC generates the formation of superoxide (O2•−), which induces the formation of hydrogen peroxide (H2O2) and ˙OH radical. ROS induces the inactivation of phosphatase and tensin homolog (PTEN) and prolyl hydroxylases (PHDs) as well as cell death by apoptosis through mitochondrial translocation of p53. Abbreviation: Epidermal growth factor (EGF), phosphoinositide 3-kinase (PI3K), hypoxia-inducible factor 1 (HIF-1), superoxide dismutase 1,-2 (SOD1,-2). Figure was created with BioRender.
Principal functions of the Krebs cycle include the generation of NADH and FADH2, which are subsequently used in Complex I, III, and II of the electron transport chain, respectively, as well as the synthesis of precursors such as oxaloacetate (OA), citrate (CIT), α-ketoglutarate (αKG), succinyl-CoA (Su-CoA), and fumarate (FM) for the formation of amino acids, cholesterol, fatty acids, and biological membranes biosynthesis (Marquez et al. 2019; Yang et al. 2016).
Intriguingly, Krebs cycle-derived metabolites present signaling functions and impact critical processes for immune cell activation and cellular transformation. For instance, acetyl-CoA is considered an epigenetic regulator through the acetylation of histones; α-ketoglutarate is required as a cofactor for many histone and DNA demethylases while succinate and fumarate are competitive inhibitors of these demethylases (Boukouris et al. 2016). Whereas, oxaloacetate inhibits proto-oncogenic and pro-glycolytic factors such as HIF-1 and AKT (Eniafe and Jiang 2021). Kuang and colleagues reported that OA induces apoptosis, inhibits the transcription and activity of glycolytic enzymes such as hexokinase (HK2), phospho-fructokinase2 (PFK2), and lactate dehydrogenase (LDH) (Kuang et al. 2018), and increases the TCA cycle and oxidative phosphorylation by increasing the transcription of PDH, Citrate synthase, IDH, COX I, and COX II through the inhibition of the AKT/HIF and c-myc signaling pathway (Kuang et al. 2018). OA binds to the 2-oxoglutarate site of FIH and induces the inactivation of HIF-1 hydroxylation leading to HIF-1α-mediated gene expression (Lu et al. 2005). Also, it has been reported that OA and malonate are inhibitors of succinate dehydrogenase (SDH) (or complex II of OXPHOS) (Stepanova et al. 2016).
2.1 Krebs cycle in glioblastoma
Glioblastomas are highly glycolytic tumors that produce enough metabolites and ATP to support cell growth and survival. Marin and coworkers used an orthotopic mouse model of primary human glioblastoma and infused 13C-labeled nutrients into mice bearing three independent GBM lines to identify the metabolic fates of glucose. They evaluated glycolysis, the TCA cycle, and biosynthesis of amino acids and found 13C signal in many metabolites, including glutamate, glutamine, aspartate, and γ-aminobutyric acid (GABA). Moreover, the label was found in C4 of glutamate and glutamine apparently, as a consequence of the activity of pyruvate dehydrogenase (PDH), demonstrating normal turnover of the TCA cycle in the tumors (Marin-Valencia et al. 2012). The label of 13C in glutamate is linked to the TCA cycle through αKG, the main precursor of glutamate, which receives an amino group by transamination to become glutamate. Other metabolites such as citrate, glutamate, malate, and aspartate were highly enriched in 13C (Marin-Valencia et al. 2012), demonstrating that oxidation in the TCA cycle is a significant fate of glucose carbon (Jensen et al. 2008; Obukhova et al. 2022). Therefore, GBM cells utilize mitochondrial glucose oxidation during tumor growth in vivo.
Then, the TCA cycle is a flexible central provider for the catabolic and anabolic processes of the glioma cell (Nelson et al. 2017). Moreover, citrate generated by the TCA cycle is converted into Acetyl-CoA and OA by ATP citrate lyase (ACL) for fatty acids and cholesterol synthesis in the pseudopodia of U87 glioma cells (Beckner et al. 2010). Conversely, OA is metabolized by phosphoenol pyruvate carboxykinase (PEPC-1) to PEP, a gluconeogenic precursor.
Under nutrient-limiting conditions and aggressive tumor growth, glioma cells can also use the TCA (Maher et al. 2012). This adaptation may be important for incorporation into the TCA to meet the high biosynthetic and bioenergetic demands of malignant GBM growth (Mashimo et al. 2014). Moreover, multiple metabolic intermediates provided from the catabolism of macromolecules can be incorporated into the TCA (Jochmanova and Pacak 2016). For instance, Acetyl-CoA is obtained by glycolysis, β-oxidation, and ketolysis. Glucose contributes less than 50 % of the acetyl-CoA pool in human brain tumors, which upregulates the expression of hexokinase 2 and LDH (Mashimo et al. 2014). While in ketolysis, acetate is converted to Acetyl-CoA by acetyl-CoA synthetase 2 (ACS2), which is overexpressed in human glioblastoma samples and correlates with shorter survival rates and the induction of lipogenesis via TCA cycle activation (Mashimo et al. 2014).
It has been demonstrated that pyruvate obtained from glucose is converted to OA by pyruvate carboxylase in SF188 glioma cells, refilling the pool of precursor molecules of lipids, proteins, and nucleic acids to activate the TCA (Cheng et al. 2011). Oppermann and coworkers reported that U87 glioma cells cultured with pyruvate without glucose produced higher levels of TCA cycle metabolites such as citrate, α-ketoglutarate, succinate, malate, and oxaloacetate, as well as a higher concentration of alanine, aspartate, and ribose-5-phosphate, demonstrating the high plasticity of glioblastoma cells to modify the nutritional supply in the tumor microenvironment (Oppermann et al. 2016). On the other hand, the NAD derived from pyruvate can activate cytosolic MDH1 to generate OA from malate and promote aspartate synthesis through glutamic-oxaloacetic transaminase 1 (Jensen et al. 2008). Also, malate can exit the mitochondria and contribute to the formation of pyruvate in a reaction catalyzed by the malic enzyme that generates NADPH and subsequently lactate production by lactate dehydrogenase (LDH) (Jensen et al. 2008).
In addition, it has been demonstrated that the decrease in glucose inhibits the pyruvate transporter and stimulates the synthesis of αKG by glutaminolysis (Yang et al. 2014), whereas glutamine may be converted to glutamate by glutaminase (GLS), which is metabolized by glutamine dehydrogenase (GDH) to αKG and ammonia for TCA cycle anaplerosis (Connor et al. 2005). In SF188 glioblastoma cells, glucose deprivation is accompanied by a large increase in the activity of glutamate dehydrogenase (GDH) (Yang et al. 2009). Moreover, the inhibition of GLS eradicates glioblastoma stem-like cells (GSCs), which are responsible for therapy resistance and tumor recurrence (Koch et al. 2020).
On the other hand, some mutations contribute to cancer development and progression by disrupting cell metabolism and altering the epigenetic landscape. These mutations are present in genes encoding enzymes of the TCA cycle (Huang et al. 2019). Dominant defects associated with oncogenesis were described in cytosolic and mitochondrial isoforms of three nuclear-encoded enzymes: succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase (Cardaci and Ciriolo 2012). Also, epigenetic regulator genes have been identified as key drivers of subtypes of gliomas, being the most common mutations in IDH1 or IDH2 in lower-grade gliomas, and histone three mutations in pediatric high-grade gliomas (Ostrom et al. 2021). Therefore, altered cellular metabolism, including glioma, is a hallmark of cancer cells (Hanahan and Weinberg 2011). These metabolic adaptations in glioma appear to be responsive not only to the tumor’s genotype but also to the biochemical microenvironment (Bi et al. 2020).
2.2 TCA enzymes in glioma
2.2.1 Citrate synthase citrate synthase
Citrate synthase (CS) is designated as the first enzyme of the Krebs cycle and catalyzes the irreversible condensation of acetyl-CoA with oxaloacetate to form citrate (Ciccarone et al. 2019). Its activity is inhibited by ATP, NADH, and derived fatty acids. Citrate synthase was significantly downregulated in glioblastoma compared to low-grade gliomas (Fan et al. 2020), indicating its probable role in aggressiveness. In experiments of mitochondria transplantation in U87 glioma cells, the expression of CS was increased with a diminished Warburg effect, which promotes an inhibition in cell viability and induction of the mitochondrial apoptotic pathway (Sun et al. 2019). In T98G cells cultured in DMEM medium with galactose, a higher respiration rate, citrate synthase activity, and citrate accumulation are more susceptible to apoptosis when treated with 4-phenyl-5-(4-nitro-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride (MI-D), impairing mitochondrial oxidative phosphorylation compared to cells cultured in standard DMEM (Correa-Ferreira et al. 2022). It has been reported that citrate negatively regulates PDH (Taylor and Halperin 1973; Williams and O’Neill 2018) and succinate dehydrogenase activity, damaging the OXPHOS (Guo et al. 2013).
Furthermore, in three-dimensional models (spheroids), a decrease in proliferation, the size of spheroids, and formation of glioma colonies has been reported in the presence of 9 mM citrate (Ayat 2019). This correlates with the inhibition that citrate has on glycolysis (inhibitor of phosphofructokinase (PFK-1,-2), as it has been published that three-dimensional models are energetically dependent on this pathway (Rodriguez-Enriquez et al. 2008). In a breast cancer model, citrate suppresses glycolysis by decreasing PFK-1 activity, the generation of lactate and ATP, the activation of caspases-3,-9, as well as the expression of anti-apoptotic factors such as Bcl-xL, Mcl-1, and survivin (Wang et al. 2016).
Additionally, Ed Sayer et al. reported that a double inhibition of the glycolytic process by 3-bromo pyruvate (HK2 inhibitor) and citrate exerts a synergistic effect on the viability of C6 rat glioma cells and spheroids and on the clonogenic capacity of glioma cells. It also decreases migration power, with the authors suggesting that the co-treatment lowers the generation of pyruvate and, consequently, the levels of lactate, alanine, and gluconeogenic (PEP) and Krebs cycle (Acetyl-CoA and OA) precursors, inducing an energetic deficit and cell death (El Sayed et al. 2012). In glioblastoma, mitochondrial citrate is transported to the cytosol, where it is converted to acetyl-CoA by the enzyme ACL; inhibition of ACL with hydroxycitrate inhibits invasion and migration in GBM (Agnihotri and Zadeh 2016; Beckner et al. 2010). Also, citrate could suppress invasion by promoting PTEN activation, leading to AKT inactivation (Ren et al. 2017).
On the other hand, CS downregulation correlates with the decrease of pFAK, MMP-2, and vimentin, all proteins involved in migration and invasion (Chen et al. 2014). Also, citrate has been proposed as a biomarker of malignancy in pediatric glioma in a study where citrate concentration was measured in several patients, reporting a subpopulation with a high citrate concentration that correlates with greater malignancy and prognosis (Bluml et al. 2011). The mechanisms of extracellular citrate uptake, accumulation, and its release into the bloodstream could provide new targets for cancer treatments of primary brain tumors and brain metastases (Jordan et al. 2022). Thus, citrate modulates cellular mechanisms such as cell proliferation, survival, angiogenesis, migration, invasion, and cell death by regulating catabolic and anabolic pathways such as glycolysis, the TCA cycle, oxidative phosphorylation, and fatty acid synthesis (Icard et al. 2021).
2.2.2 Aconitase
The citrate produced by CS is converted to cis-aconitate, which is converted at isocitrate by aconitase (AC). Furthermore, the cis-aconitate is descarboxylated by the immune-responsive gene 1 (IRG1), also known as cis-acotinase decarboxylase to generate itaconate (Chen et al. 2019; Chun et al. 2020). Itaconate can be converted into itaconyl-CoA and subsequently at citramalyl-CoA. Citrate lyase subunit beta-like (CLYBL) catabolizes citramalyl-CoA to pyruvate and acetyl-CoA, which later re-enters at tricarboxylic acid (TCA) cycle (Li et al. 2020; Yu et al. 2019). The overexpression of aconitase has been correlated with glioblastoma malignancy, being a potential biomarker for this type of cancer (Fuentes-Fayos et al. 2019; Pan et al. 2014). IRG1 (and presumably itaconate) were also overexpressed in glioma tissue, which was associated with disease progression and bad prognosis in glioma patients (Pan et al. 2014, Ryan et al. 2019). The overexpression of IRG1 in glioma cells in both in vitro and in vivo models promotes growth, migration, invasion, and tumorigenesis. Inactivation of IRG1 by siRNA or miR-378 downregulates the regulatory proteins involved in the expression of the cell cycle (p21, CDK4/6, cyclin D1, E2F1) and epithelial mesenchymal transition (vimentin and SNAIL) as well as NF-κB and STAT3 pathway signaling (Pan et al. 2014). Low miR-378 levels have been associated with poor overall survival and worse clinicopathological parameters of glioma patients (Shi et al. 2018). Weiss et al. (2018) demostrated that resident macrophages of B16 melanoma and ID8 ovarian peritoneal tumors upregulates the transcription and transduction of IRG1 inducing the itaconate release, which induces an accumulation of itaconate in tumor cells and a potentiation in the pro-tumoral effect in the peritoneum. The itaconate in the macrophages increase the OXPHOS activity by oxidation of fatty acids and in turn generation of mitocondrial ROS, which promotes the activation of ERK, which could modulates the cell proliferation in vivo. The authors suggesting a crosstalk between tumor cells and resident macrophages in the tumoral microenviroment, whereas cancer cells can induces the expression of IRG1 in the macrophages promoting the generation of itaconate followed macrophage polarization leading tumor growth (Weiss et al. 2018). Also, it has been demonstrated that miR-378 suppress the tumoral growth of prostate cancer through ERK inhibition (Chen et al. 2016) and IRG1 to activate at STAT1/3 signaling via ROS derives pro-inflammatory cytokine productions (Liu et al. 2017, Wu et al. 2020). In addition, it has been demonstrated that IRG1 and itaconate induces the accumulation of succinate via SDH inhibition (Cordes et al. 2016). High succinate concentrations act as a pro-inflammatory signal that promotes the release of IL1 β and stabilization of HIF-1 (Lampropoulou et al. 2016).
In contrast, Kimura et al., reported that the co-administration of M4N (global transcription inhibitor) plus TMZ in xenograft mice with human GBM LN229 cell line suppress the tumoral growth by reduces the glycolytic pathway by LDH inactivation and TCA cycle as well as reduction in the lactate and 2-hydroxyglutarate levels. But observed a higher significantly increases of itaconate in LN229 tumors and macrophages infiltrated in the TME. The authors suggesting that itaconate presents in the tumors is derived of the macrophages. Furthermore, the itaconate can inhibit the inflammation and enzymes involves in the glycolysis and TCA cycle in the cells that form the tumor mass including tumor cells, which promotes a reduction in the aggressive of GBM cells (Kimura et al. 2023). It has been reported itaconate blocks the glycolytic flux by the inactivation of GA3PDH by direct alkylation on cys residues of protein (Liao et al. 2019). Also, the itaconate induces the alkylation (inactivation) of two cysteines residues of aldolase A, reducing the lactate levels, extracellular acidification rate, and increasing the oxidative phosphorylation, thereby activating the anti-inflammatory process in macrophages stimulated with LPS through the inhibition of IL1β production (Liao et al. 2019). The activation of macrophages with LPS causes induction and activity of IRG1-producing itaconate, which shows strong immunosuppressive properties (Swain et al. 2020). The pre-treatment of murine bone marrow-derived macrophages (BMDMs) with dimethyl itaconate (DMI) before LPS stimulation decreases the transcription of pro-inflammatory genes such as iNOS, IL1β, IL12, IL6, and IL18 as well as low HIF-1α protein levels. However, BMDMs (Irg1−/−) do not generate itaconate showing high levels of NO, ROS, IL1β, IL6, IL12, IL18, and HIF-1α concerning wild type BMDMs (Lampropoulou et al. 2016). Also, it has been demonstrated that the administration of DMI on colorectal cancer cells inhibits the release of IL1β and chemokine ligand 2 in intestinal epithelial cells, decreasing the infiltration of inflammatory macrophages to the tumor microenvironment and supporting a reduction in the risk of colorectal cancer development (Wang et al. 2020).
For other hand, it has been reported that mitochondrial aconitase is associated with neurodegenerative disorders (Choi et al. 2021; Khodagholi et al. 2018). The activity of aconitase has been related to other enzymes such as frataxin coded by the gene XRF, which is involved in the biogenesis of the Fe/S group. Patients with Friedreich’s ataxia syndrome present a reduced expression of aconitase due to a genetic mutation in XRF, leading to alterations in mitochondrial iron homeostasis and oxidative stress. XRF-transfected U87 glioma cells had an increase in the aconitase activity (20 %), while the activity of glutathione peroxidase and catalase decreased (65 % and 40.3 %, respectively), which induce low levels of ROS, protecting proteins with Fe/S groups. Additionally, the cells had significant resistance to severe hypoxia (0.1 % oxygen) (Kirches et al. 2011). This antioxidant effect could explain how glioma cells in oxidizing environments can induce tumor growth suppression (Kirches et al. 2011). These results suggesting that IRG1 enzyme, also shown dual roles in the glioma pathology, thereby known with more deep the function as well regulation of ARG1 in cancer cells is essential for the development of strategies therapeutic against ARG1 (Kirches et al. 2011).
2.2.3 Isocitrate dehydrogenase
Isocitrate dehydrogenase (IDH) is an enzyme involved in many processes in the cell, including mitochondrial oxidative phosphorylation, glutamine metabolism, and lipogenesis (Nelson et al. 2017). It is a main site of control in the Krebs cycle due to its allosteric regulation (Hu et al. 2006). IDH catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG) and plays an important role in the reduction of NADP+ to NADPH (Nelson et al. 2017). IDH1 and IDH2 can also run in the “reverse” direction to produce isocitrate, which can be used for lipid synthesis. There are three isoforms of the enzyme: two dependent on NADP+ (IDH1 and 2, homodimers) located in the cytosol and mitochondrial matrix, respectively; and one isoform dependent on NAD+ (IDH3) existing as a heterotetramer in the mitochondrial matrix. Five genes encode three human IDH catalytic isozymes: IDH1, IDH2, and IDH3 (Cohen et al. 2013, Ramachandran and Colman 1980). IDH1 is present in the cytosol and peroxisomes and has antioxidative effects, while IDH2 is present in mitochondria (Kurmi and Haigis 2020).
It has been reported that overexpression of IDH1 and its product in glioma cells promotes the development and aggressiveness of brain tumors. IDH1 wild-type primary GBM regulation of invasion and migration relies on PI3K/AKT/mTOR activation and its effects on the IDH1/αKG axis and upregulation of SNAIL (E-cadherin repressor), N-cadherin, and vimentin expression. The authors suggest that α-ketoglutarate modulates the PI3K/AKT/mTOR signaling pathway due to the administration of rapamycin (mTOR inhibitor) suppressing the phosphorylation of AKT and mTOR as well as the migration of U87 cells that overexpress IDH1 and are treated with α-ketoglutarate (Shen et al. 2020). Furthermore, Wang et al. demonstrated that GDH1 activates NF-kB in low concentrations of glucose by binding to the p65/IKKβ complex and generates αKG, which also activates IKKβ and in turn phosphorylates IκBα, activating NF-κB. NF-kB promotes GLUT1 transcription, favoring glucose uptake and increasing lactate levels, consequently promoting gliomagenesis in vivo (Wang et al. 2019).
On the other hand, it has been proposed that αKG is an endogenous tumor suppressor metabolite (Chin et al. 2014; Fu et al. 2015). In this sense, microRNA-183 was upregulated in several types of gliomas and has a complementary sequence to IDH2, thus diminishing IDH2 expression and αKG levels with subsequent upregulation of HIF-1α and LDHA (Tanaka et al. 2013). The authors suggest that αKG can induce the degradation of HIF-1 by promoting PHD2 activation and inhibiting the carcinogenic process by glycolysis inhibition (Zdzisinska et al. 2017). Additionally, αKG regulates several enzymes. For instance, αKG inhibits ATP synthase and reduces ATP levels, inducing mTOR signaling inhibition by activating AMPK, leading to reduced cell proliferation and tumor cell death (Fu et al. 2015). Also, Lee et al. demonstrated that treatment with dimethyl alpha-ketoglutarate (DAKG), an αKG precursor, in diffuse intrinsic pontine glioma cells with H3.3K27M mutation inhibits cell proliferation and colonies and neurosphere formation by inducing arrest in the G1/S phase, inhibiting the acetylation of H3.3K27M and phosphorylation of ERK and AKT, as well as downregulating CBP/p300, c-myc, and ATF1 levels. The authors suggest that the inactivation of the kinases can induce the degradation of c-myc, transcriptional inactivation of ATF1, and a decrease in the acetyltransferase and transcriptional capacity of p300 (Lee et al. 2023). αKG also serves as a co-substrate for a large family of 2-oxoglutarate-dependent dioxygenases (2-OGDDs) such as Jumonji C-domain containing histone demethylases (JMJDs) and the 10–11 translocation (TET) family of 5mC hydroxylases with functions in cellular processes such as hypoxic response and epigenetic regulation (Abla et al. 2020; Ryan et al. 2019).
Additionally, it has been reported that the lethal effect of gabapentin (branched-chain amino acid transaminase 1 (BCAT1) inhibitor) on glioma human tumors was synergistically increased by αKG, altering the NAD+/NADH ratio, inhibiting mTORC1 activity and, in turn, nucleotide and protein synthesis as well as ATP levels (Zhang et al. 2022). In addition, IDH1 and IDH2 heterozygous point mutations confer a new metabolic enzymatic activity that produces an oncometabolite (e.g., 2HG, from α-ketoglutarate) (Nam et al. 2014). There has been reported a link between IDH1 or IDH2 mutations and reprogrammed metabolism for predicting prognoses for several types of cancer (Jezek 2020; Mustafa et al. 2014). IDH1 mutations are present in 81.6 % and 82 % of grade II and III gliomas, respectively (Cohen et al. 2013). Additionally, it has been reported that patients with IDH1 (arginine to histidine residues, R132H for IDH1) mutations are associated with longer survival than patients with glioblastomas without IDH1 mutations (Alzial et al. 2022; Kloosterhof et al. 2011; Molinaro et al. 2019; Parsons et al. 2008). The mechanism by which glioma patients with IDH1 mutations were associated with 1 year of improved survival may be due to the generation of NADPH, which is impaired in IDH1R132 mutants; in addition, the velocity of consumption of NADPH is higher than their production and, finally, the low NADPH levels sensitize glioma to chemotherapy and irradiation, allowing greater general patients’ survival (Bleeker et al. 2010). Also, it has been observed that low-grade gliomas (LGG) can present mutations in isocitrate dehydrogenase (IDH), which lead to the production of the oncometabolite 2-hydroxyglutarate (2HG) that decreases the activity of DNA demethylases through the inhibition of TET2. Then, it has been reported an increase in the methylation of LDHA and programmed cell death ligand 1 and 2 (PDL1/2) promoters, which results in a decrease in glycolysis and correlates with lower levels of PDL1/2, which is a molecule expressed by T cells that usually inhibits the inflammatory/immune response. Directly, PD1 and its ligand PDL-1 inhibit T-cell activation by preventing TCR signal transduction; PD1, an immunoreceptor, contains a tyrosine-based switch motif (ITSM), which recruits phosphatases containing SH2 domains (SHP1 and SHP2). This motif is phosphorylated in response to antigen presentation causing binding of PD1/PDL1 and, therefore, inhibiting TCR signal transduction by the SHP-mediated dephosphorylation of the TCR signalosome as CD3ζ, ZAP70 and PI3K kinases, which leads to the inactivation of the downstream cascade (Zuazo et al. 2017). This phenomenon (inhibition of inflammatory/immune response) correlates with better survival in LGG with IDH mutated compared to those with IDH wild type and shows an association between glycolytic metabolism and activation of an immune response (Givechian et al. 2021). Also, Chesnelong and colleagues reported that the suppression of LDHA due to an increase in the methylation of IDH promoter in mutant gliomas and brain tumor stem cells derived from IDHmt tumors showed reduced glycolysis, which can contribute to slow proliferation cell and better prognosis compared to IDH wild type gliomas and higher LDHA levels, respectively. It suggests that silencing of LDHA depends on IDHmt and the downregulation of glycolytic genes such as HK2, PGK1, ENO1, PKM2, LDHA, and PDK1 can be dependent on HIF-1α degradation and inactivation of histone demethylase Jumonji domain 2C, both pathways inhibited by 2-hydroxyglutarate, the product of the neomorphic activity of the IDHmt enzymes (Chesnelong et al. 2014). These studies indicate that LDHA regulates not only glycolysis but also cell survival (Chesnelong et al. 2014).
Recently, the role of IDH1 mutations in cancer progression and clinical outcome of GBM has been elucidated (Alzial et al. 2022). It has been reported that 2HG promotes gliomagenesis and shows a 100-fold increased concentration in patients with IDH1 or IDH2 mutations (Bunse et al. 2018; Nam et al. 2014). This increased concentration of 2HG competitively inhibits α-KG binding to histone demethylases, thus blocking the differentiation of glioma cells (Lu et al. 2012; Xu et al. 2011). In this sense, the overexpression of TET2 in LN229 glioblastoma cells induces inhibition of cell viability in vitro and tumoral proliferation in vivo, related to the upregulation of genes involved in neuronal differentiation (Garcia et al. 2018). Furthermore, 2HG induces tumorigenesis by suppressing endostatin, an angiogenesis inhibitor, which leads to tumor vascularization and glioma growth (Liu et al. 2012). Additionally, 2HG has an essential role in the immune system. 2HG diminishes the levels of STAT1, a regulator of the chemokine CXCL10 (also known as IP-10), the key factor in the attraction of CD8+ cytotoxic T cells. Thereby, 2HG reduces the CD8+ T-cell infiltration at the tumor tissue from syngeneic mouse gliomas (Reiter-Brennan et al. 2018). In addition, 2HG partially correlates with a minor infiltration of immunosuppressive cells (T-Regs) and tumor-associated macrophages (TAMs) in IDH mutant gliomas than in wild-type (Berghoff et al. 2017). Furthermore, IDH2 mutation can induce nuclear accumulation of β-catenin and upregulates vascular endothelial growth factor (VEGF) to promote tumor microenvironment formation and produces high levels of HIF-1α to promote glycolysis, glioma invasion, and chemoresistance, manifested as a search for glutamate (Huang et al. 2019; Lenting et al. 2019; van Lith et al. 2014). On the other hand, one study indicates a model in which these mutant gliomas exist in symbiosis with accessory cells as astrocytes (or other neuronal lineages) supporting lactate and glutamate for cancer maintenance (Lenting et al. 2019). Although there have been attempts to inhibit IDH, clinical data have shown that inhibition of mutant IDH may decrease the growth of less aggressive, non-enhancing IDHmt low-grade gliomas but is less effective for higher-grade, contrast-enhancing IDHmt gliomas (Mellinghoff et al. 2020), suggesting that inhibition of IDH is only effective in low-grade gliomas (Scott et al. 2021). Thus, it is important to find specific clinical strategies to provide customized therapies.
2.2.4 α-ketoglutarate dehydrogenase
α-ketoglutarate dehydrogenase (α-KGDH) comprises three proteins, each encoded on a different and well-characterized gene (Sheu and Blass 1999). This enzyme is composed of multi-enzymatic complexes with multiple copies of three subunits: 2-oxoglutarate decarboxylase TPP-dependent (E1), the enzyme dihydrolipoamide succinyl transferase (E2), and dihydrolipoyl dehydrogenase (E3). αKG undergoes oxidative decarboxylation to form succinyl CoA (Su-CoA), catalyzed by α-KGDH (Sheu and Blass 1999), whereas succinyl CoA is an allosteric inhibitor of α-KGDH and a precursor of the formation of succinate and ATP generation (Sheu and Blass 1999).
In the human brain, the activity of α-KGDH is lower than that of any other enzyme of energy metabolism, including phosphofructokinase, aconitase, and the electron transport complexes (Sheu and Blass 1999). α-KGDH deficiency is a rare inborn error related to neurodegenerative disorders derived from this deficiency (Dunckelmann et al. 2000). On the other hand, it has been reported that α-KGDH is located in the nucleus of U251 glioma cells to bind to lysine acetyltransferase 2A (KAT2A), also known as GCN5, in the promoter regions of its genes. Furthermore, KAT2A also binds to succinyl-CoA generated by α-KGDH, promoting the histone three succinylation in lys79, regulating the gene expression of more than 7,000 genes. KAT2A low expression or inhibition in the α-KGDH nuclear translocation reduces tumor cell proliferation and GBM tumor growth (Wang et al. 2017). Accumulation of αKG due to α-KGDH inactivation triggers TET1 and TET3 protein expression and activities limiting cell migration and epithelial-mesenchymal transition in cancer cells (Abla et al. 2020). Also, it was observed that depletion of the E2 subunit from the α-KGDH complex in human neuroblastoma cells inhibits cell proliferation and induces G1 arrest cycle and apoptosis by lower NADH levels and in turn suppresses the OXPHOS. The authors suggest that inactivation of the α-KGDH enzyme promotes a diminishment in the succinyl-CoA levels and in turn a decrease in NADH generation and ETC activity (Anderson et al. 2021). On the other hand, High E2 subunits levels of α-KGDH are correlated with aggressive disease and poor survival in neuroblastoma patients (Anderson et al. 2021). These findings suggest an important role of α-KGDH in the glioma development through metabolic activity but also as a modulator in cell signaling by post-translational and transcriptional levels through succinylation of proteins (Anderson et al. 2021). The lysine succinylation of cellular proteins by succinyl-CoA and succinate induces a significant change in the structure and function of proteins (Tannahill et al. 2013; Zhang et al. 2011).
Thus, protein succinylation plays an important role in tumorigenesis. In this sense, Zhang et al. demonstrated that the succinylation at Lys40 of TAGLN2 actin-binding protein in U87 glioma cells promotes growth, migration, and tumoral angiogenesis (Zhang et al. 2023). Also, it has been reported that the succinylation in Lys311 on PKM2 stimulates its tetramer to dimer transition and nuclear accumulation promoting the release of IL1β (Wang et al. 2017). Nuclear PKM2 forms a complex with HIF-1α inducing IL1β transcription (Wang et al. 2017). On the contrary, PKM2 is desuccinylated through mitochondrial SIRT5, decreasing the IL1β generation as well as the pro-inflammatory response in macrophages (Wang et al. 2017).
2.2.5 Succinyl CoA synthetase
The enzyme succinyl CoA synthetase (SCS) catalyzes the reaction forming succinate from succinyl CoA. The enzyme SCS uses succinyl-CoA to phosphorylate ADP or GDP (Nelson et al. 2017). There are two mitochondrial isoforms of the α and β heterodimer: one isoform that phosphorylates ADP (SCS-A) and the other that phosphorylates GDP (SCS-G). Its specificity appears to depend on the β subunit. SCS-A is proposed to support the forward reaction while SCS-G catalyzes the reverse reaction that participates in heme synthesis and ketone bodies activation (Furuyama and Sassa 2000). High levels of expression of the α subunit (SCS-A) and β subunit (SUCLA2) from SCS are present in the brain (Lambeth et al. 2004).
It has been suggested that the deficiency or inactivation of SCS can participate in the pathogenesis of metabolic disease and cancer (Lancaster and Graham 2023). In this sense, it has been reported that the phosphorylation at Ser79 SUCLA2 by p83 MAPK under oxidative stress promotes the release of SCS from GLS, which inactivates the transformation of succinyl-CoA to succinate and in turn increases the succinyl-CoA level, thereby inducing the succinylation at Lys311 GLS, which enhances the oligomerization and activity of GLS and thus the glutaminolysis that increases the generation of NADPH and glutathione, thereby decreasing oxidative stress and stimulating tumoral growth (Tong et al. 2021). Additionally, the absence of SUCLG2 protein was observed as a decrease in the SDH activity promoting damages in respiration and accumulation of succinate oncometabolite due to SDHB decreases and disassembly of complex II of ETC in hPheo1 cell line and pheochromocytoma and paraganglioma (PPGL) patients samples with mutated SUCLG2. The authors suggest that SUCLG2 genic alterations can compromise the SDH activity (Hadrava Vanova et al. 2022).
2.2.6 Succinate dehydrogenase
This enzymatic complex (also known as Complex II, succinate-ubiquinone oxidoreductase) is localized in the mitochondrial inner membrane and is also classified as a tumor suppressor. SDH is a mitochondrial enzyme with dual function in the Krebs cycle (oxidation of succinate to fumarate and release of fumarate in the inner mitochondrial membrane) and in the electron transport chain (reduction of ubiquinone, coenzyme Q, and release of ubiquinol into the inner membrane) whose complexes are encoded by nuclear genes (Dalla Pozza et al. 2020; Rasheed and Tarjan 2018). Four subunits comprise functional domains of SDH (A, B, C, and D); subunits A and B form the main catalytic domain involved in the oxidation of succinate to fumarate, while subunits C and D participate in the electron transport chain to generate mitochondrial ATP (Rasheed and Tarjan 2018). Recently, SDH has been considered responsible for tumor progression and referred to as a tumor suppressor because subunit mutation can lead to different tumor types such as head and neck paragangliomas, thyroid cancer, or gastrointestinal and renal cell carcinomas (Zhao et al. 2017). Mutations in the SDHA gene on chromosome 5p15.33 are related to the presence of patients with paraganglioma and pheochromocytoma. It has been suggested that SDH mutations can contribute to the invasive phenotype in glioblastoma through the inactivation of PHDs and Jumonji C histone demethylases and TET 5 methylcytosine hydroxylases, which induce HIF-1α stability as well as aggravating epigenetic dysregulation, respectively (Chinopoulos and Seyfried 2018; Garcia et al. 2021; Her and Maher 2015). Sharpe et al. reported diminished SDH catalytic activity in GBM tumors, and then high concentrations of succinate correlated with a poor prognosis (Sharpe et al. 2017). 2-DG, a glucose analog, decreases the proliferation of glioma cells under hypoxia, inducing cell differentiation, higher activity of SDH, and degradation of HIF-1α. However, when succinate is incorporated, it induces the production of ROS and causes a strong stabilization of HIF-1α, promoting cell growth and inhibition of apoptosis in glioma cells (Pistollato et al. 2010). Furthermore, grade III glioma with high IDH1 levels and low glutamate dehydrogenase1,-2 and SDHA/SDHB levels are associated with poor outcomes due to these alterations inducing a high mitochondrial flux, promoting the generation of ROS and succinate, which induces HIF-1 activation and the Warburg effect in glioma cells (Sharpe et al. 2017). On the other hand, it has been reported that the inactivation of SDH by 2HG produced by IDH mutated glioma cells promotes high levels of mitochondrial hypersuccinylation due to the production of succinyl-CoA via succinate, thereby inducing glycolytic metabolism and apoptotic resistance via increases of lactate, pyruvate/citrate rates, and mitochondrial Bcl-2, whereas SIRT5 as well as glycine inhibit the hypersuccinylation and tumoral growth (Li et al. 2015). Glycine can lower the levels of succinyl CoA by reacting with succinyl-CoA to give 5-aminolevulinate, a precursor of the heme group (Li et al. 2015). It has been reported that the succinate accumulated as a result of SDH inhibition participates as a carcinogenic initiator and inflammatory signal (Zhao et al. 2017). Succinate induces a pro-inflammatory response and metabolic shift from oxidative phosphorylation to glycolysis in macrophages by promoting the activation of HIF-1α, which positively regulates the transcription of IL1β, PDH kinase 1 (PDHK1), and PDK3 (Tannahill et al. 2013). High levels of succinate inhibit PHD activity leading to the release of HIF-1 from pVHL, thereby promoting the stabilization and activation of HIF-1α (Selak et al. 2005; Tannahill et al. 2013). Furthermore, cancer cells with defective SDH activity stimulate tumor proliferation by stopping the anti-tumor immune responses through the release of succinate into their microenvironment, which activates the succinate receptor (SUCNR1) localized on the cell surface of macrophages, triggering the PI3K/HIF-1 signaling which positively regulates the gene transcription of tumor-associated macrophages (TAM) markers such as arginase 1 (Arg1), fizz1, mgl-1,-2, inducing TAM polarization (Wu et al. 2020). On the other hand, succinate, through autocrine signaling in cancer cells, binds to SUCNR1 promoting its migration, EMT, and invasion by decreasing E-cadherin expression and increasing the transcription of N-cadherin, vimentin, and SNAIL transcription factor by activation of the PI3K/AKT/HIF-1 signaling (Wu et al. 2020). Thus, succinate transmits an “oncogenic” signal that induces the transcription of genes that promote glycolysis, inflammation, angiogenesis, migration, and metastasis, leading to tumor formation and progression (Selak et al. 2005).
2.2.7 Fumarase
Fumarase (or fumarate hydratase, FH) is a key enzyme in the Krebs cycle located in the mitochondrial matrix and catalyzes the reversible reaction of dehydration of l-malate to fumaric acid. There are two isoforms of FH: mitochondrial and cytosolic, products of only one gene by alternative splicing. The cytosolic version can be involved in the urea cycle and amino acid metabolism (Yogev et al. 2011). FH is considered a tumor suppressor because mutations can predispose tissues to malignant transformation due to the inactivation of FH (Chinopoulos and Seyfried 2018). Germline mutations in fumarate hydratase induce the loss of its activity, promoting a predisposition to the initiation and metastasis in a subset of pheochromocytomas (PCC) and paragangliomas (PGL) via fumarate accumulation and global changes in DNA methylation and protein 2-succination (Castro-Vega et al. 2014). Fumarate directly or indirectly induces the activity of HIF-1α via inhibition of PHDs as well as 2-oxoglutarate-dependent dioxygenases such as JMJC and TET and complexes I and II of ETC (Hoekstra et al. 2015; Laukka et al. 2016; O’Flaherty et al. 2010; Tyrakis et al. 2017). Also, fumarate can induce protein succination by reacting with thiol groups from Cys residues of proteins, generating a stable thioether known as S-(2-succino) cysteine (Alderson et al. 2006).
On the other hand, it has been reported that monomethyl fumarate (MMF, a derivative of fumarate) reduces the migration of glioma cells and increases the toxicity of TMZ and ionizing radiation (Booth et al. 2014). Also, it has been demonstrated that MMF/DMF enhance the therapeutic effect of fingolimod and proteasome inhibitors such as velcade and carfilzomib on glioma cells (Booth et al. 2014; Dent et al. 2020). The antineoplastic effect of the combinations involves the formation of ROS, inactivation of survival pathways (ERK, AKT, NF-κB, STAT3, -5, and YAP), the induction of autophagy (mTOR inactivation) and activation (ATM, AMPK, ULK, Beclin1, ATG5, and ATG13), and apoptosis via the death receptor CD95/FADD/caspase-8 signaling activation and decreases of anti-apoptotic proteins (cFLIP, BclxL, and Mcl-1) (Booth et al. 2014, Dent et al. 2020). The trial NCT02337426 demonstrated the safety of DMF in patients who carry newly diagnosed GBM combined with the standard of care Stupp protocol (Shafer et al. 2020).
2.2.8 Malate dehydrogenase
Malate dehydrogenase (MDH) is an enzyme that belongs to the NAD-dependent dehydrogenases and catalyzes the conversion of malate to oxaloacetate (Minarik et al. 2002). Two isoforms have been described, distinguished by their intracellular compartmentalization (mitochondrial and cytosolic), both participating in the malate/aspartate shuttle. MDH1 cytosolic was almost undetectable in glioblastoma from patients (Lages et al. 2011). Because MDH2 is an essential enzyme in the TCA cycle, mutations are rare events that cause severe hypotonia, psychomotor delay, and refractory epilepsy, principally causing the accumulation of malate, fumarate, and lactate in the blood and cerebrospinal fluid, triggering susceptibility to pheochromocytoma and paraganglioma (Ait-El-Mkadem et al. 2017).
On the other hand, He et al. reported that high levels of malate dehydrogenase degradation helper (MDHDH) are negatively associated with glioma WHO grade and positively correlated with overall survival in patients, whereas MDHDH overexpression in U251 and U87 glioma cells induces the degradation of MDH2 via proteasome, thus altering the NAD+/NADH ratio, inhibiting glycolysis, and promoting inhibition of cell proliferation, migration, and invasion as well as autophagy via mTOR inhibition and apoptotic cell death in vitro and in vivo (He et al. 2022).
Malate contributes to redox homeostasis; this is important in cancers with RAS mutations because the tumor cells have a high concentration of ROS (Eniafe and Jiang 2021), so MDH is an alternative route for NAD regeneration in the cytosol. Also, malate accumulation is essential for cancer growth by contributing to elevated glycolytic flux due to malate functioning as a carbon source for glycolysis and biomass (Hanse et al. 2017).
2.3 TCA cycle as a target of therapeutic drugs in gliomas
The mitochondrion plays a pivotal role in the cell: in bioenergetics, biosynthesis, cell signaling, and in the development and pathology of different cancers (Marquez et al. 2019). Therefore, some targets inside the TCA can be used to overcome cancer resistance and proliferation. In glioma models exposed to the presence of metabolites related to CS, such as oxaloacetate in combination with temozolomide or citrate with 3-bromopyruvate (3BP), an increase in patient survival was observed (15 %) without apparent side effects while in vitro decreased the viability cellular (Conway and Cash 2017; El Sayed et al. 2012).
It has been proposed a treatment with 2-fluorocitrate that irreversibly inhibits the enzyme aconitase resulting in a significantly decreased carbon flux in the glial TCA cycle and decreased cellular proliferation (Galeffi and Turner 2012; Kang et al. 2021). In addition to this therapy, it has been combined with a drug that induces oxidative stress (DAO), 3-bromopyruvate (3BP), and citrate; this therapy inhibited the growth of C6 cells, angiogenesis (decreasing the number of branch points vascular and shortening the length of vascular tubules), and colony formation (El Sayed et al. 2012).
Another potential target for glioma treatment is IDH. IDH mutations in secondary glioblastoma indicate recurrence and malignant transformation (Han et al. 2020). Pharmacological inhibitors of IDH mutants include the small molecules ivosidenib and vorasidenib. In a clinical study, both drugs targeted an IDH-1 mutant in GBM and demonstrated CNS penetration and lowered 2-HG levels in tumor tissue compared with the control (Tejera et al. 2020). However, some side effects remain to overcome as hypermethylation phenotype in glioma cells (Turcan et al. 2012). Other non-pharmacological inhibitors targeting IDH mutants include a) redox imbalance (increased oxidative burden and inhibiting antioxidative response); b) immunotherapy (2HG is a potent inhibitor of antitumor T cell immunity in glioma and an inhibitor of IDH- mutant BAY1436032 manages to restore CD4+ T cell proliferation), c) DNA repair enzymes, or d) epigenetic modulators (Han et al. 2020).
Another proposed alternative treatment in GBM is the reduction of succinate (since it stabilizes HIF-1α and increases the fraction of CSC) by adding 2-DG that inhibits anaerobic glycolysis altering the phenotype of GBM. Therefore, GBM cells are forced to enter mitochondrial metabolism and differentiation (Han et al. 2020; Pistollato et al. 2010).
Besides, the antitumor and neuroprotective activity of dimethyl fumarate (DMF) over GBM has been reported. It has been determined that DMF reduced glioblastoma proliferation, decreased NF-κB expression, and restricted CSC growth; it also modifies the levels of glutathione (GSH) that can induce the expression of the anti-inflammatory protein HO-1 (heme oxygenase-1) (Ghods et al. 2013); suggesting that DMF may be considered for further antitumor studies and provide a new treatment modality for brain tumors in vitro (Ghods et al. 2013). DMF has been combined with radiotherapy and temozolomide in patients in the early stages of the disease, increasing their survival rate (8.7 months) (Shafer et al. 2020). Although several strategies have been proposed for the inhibition of the Krebs cycle enzymes, most of them have been found in vitro assays and very few in patients; however, the reports that have been published have shown that the enzymes of mitochondrial metabolism can be a successful therapeutic target for gliomas.
3 Electron transport chain and oxidative phosphorylation
Mitochondria play a pivotal role in the generation of adenosine triphosphate (ATP) required for multiple cell functions such as the synthesis of nucleic acids or proteins, ion transport through the membrane, nervous transmission, absorption of necessary molecules, excretion of undesirable substances, and muscular contraction (Duchen 2004). Mitochondria are constituted by two membranes, one externally oriented to the cytoplasm and the internal membrane, located between the intermembrane space and the mitochondrial matrix. The internal membrane is folded and forms numerous cristae, where energy production occurs through the electron transport chain (Frey and Mannella 2000).
There are five complexes involved in mitochondrial respiration and ATP synthesis: Complex I (C–I) or nicotinamide adenine dinucleotide reduced (NADH)-ubiquinone oxidoreductase or NADH dehydrogenase, complex II (C-II) or succinate dehydrogenase, complex III (C-III) or ubiquinol-cytochrome c reductase, complex IV (C-IV) or cytochrome c oxidase (COX), and complex V (C–V) or ATP synthase (Scholte 1988).
The electron transport chain (ETC) begins when NAD+ receives the electrons generated in the TCA cycle and β-oxidation. Then, NADH is oxidized to NAD by NADH-dehydrogenase, and the electrons are transferred to ubiquinone (Ub or coenzyme Q). Ub is a relatively small molecule, localized in the mitochondrial interior membrane, and can be reduced and oxidized. The other electron acceptor site is succinate, another substrate of the TCA cycle, which transfers its electrons to SDH, a flavoprotein that transfers them to ubiquinone. This coenzyme passes electrons to the oxidoreductase cytochrome, and cytochrome c (Cyt C) accepts electron pairs. Cyt C is a small protein embedded in the membrane that transports electrons to COX and finally transfers electron pairs to oxygen, generating water (King 1966; Mitchell 1967; Scholte 1988).
Therefore, the electrochemical potential is generated as the electrons are transferred through the mitochondrial complexes. The electrochemical potential is established between the two membranes and is the force that pushes ATP synthesis (Mitchell 1967). This process involves the translocation of protons to the intermembrane space of the mitochondria, and these are used by the proton pump, the enzyme ATP synthase, to generate ATP. The passage of protons does not occur in all complexes, only in complexes I, III, and IV (Mitchell 1967).
The ATP synthase enzyme consists of two domains, one in the internal mitochondrial membrane known as F0, and the other, F1 domain in the mitochondrial matrix. When the protons are released into the intermembrane space by the complexes, as they have a positive charge, they cannot disseminate freely through the membrane but circulate by the channel localized in the F0 domain (Mitchell 1967).
ATP generation is the principal function of oxidative phosphorylation (OXPHOS); however, proliferating cells also require oxygen for the redox state and aspartate to synthesize proteins, RNA, and DNA biosynthesis. In this sense, cells with dysfunctional ETC present a decrease in NAD+ levels and aspartate (Asp) synthesis; therefore, an exogenous addition of pyruvate or aspartate is necessary to restore the NAD+/NADH ratio and proliferating capacity in these cells (Birsoy et al. 2015; Van Vranken and Rutter 2015). Pyruvate is a target of lactate dehydrogenase (LDH); it regenerates NAD+ and stimulates aspartate synthesis through MDH1 and cytosolic glutamic-oxaloacetate aminotransferase (GOT1) (Birsoy et al. 2015). Normally, aspartate biosynthesis occurs in the mitochondria through the sequential actions of MDH2 and GOT2, whereas a decrease in the NAD+/NADH ratio by ETC dysfunction inhibits MDH2 and, in turn, mitochondrial aspartate synthesis (Birsoy et al. 2015; Sullivan et al. 2015).
In addition, the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme transfers electrons directly to the ETC via ubiquinone through the oxidation of dihydroorotate (DHO) to orotate, the precursor of de novo pyrimidine and purine biosynthesis, a step essential in tumorigenesis (Bajzikova et al. 2019; Loffler 1980).
Furthermore, the ETC is necessary for the generation of glutamate and ROS. The oxidation of proline via proline dehydrogenase (PRODH) produces Δ1-pyrroline-5-carboxylate (P5C), which is converted to glutamate via P5C dehydrogenase (P5CDH), with the reduction of NAD+ to NADH. Glutamate (Glu) is metabolized to 2-oxoglutarate, succinate, and other tricarboxylic acid intermediates (Goncalves et al. 2014). PRODH also donates electrons to the ETC via FADH2, which are transferred directly to ubiquinone or to O2, generating ATP or ROS, respectively (Goncalves et al. 2014; Sawicka et al. 2022).
Moreover, approximately 0.2–2% of the electrons passing through the ETC complexes I, II, and III leak and reduce O2 to produce superoxide (O2 •−), which is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD). In the presence of copper or iron, H2O2 is transformed into OH˙ radical through the Fenton reaction (Turrens 2003). ROS contribute to genetic instability and act as a second messenger that regulates several signaling pathways controlling cell growth, survival, as well as cell death mechanisms. Similarly, oncogenic signaling positively modulates ETC activity, increasing ROS levels (Lennicke et al. 2015). ROS contribute to genetic instability and act as a second messenger that regulates several signaling pathways controlling cell growth, survival, as well as cell death mechanisms. Similarly, the oncogenic signaling positively modulates the ETC activity, increasing the ROS levels (Lennicke et al. 2015). ROS induces the inactivation by oxidation of both PTEN and prolyl hydroxylases (PHDs), resulting in PI3K/AKT signaling activation and HIF-1α stabilization in hypoxia, respectively, leading to cell survival, proliferation, and angiogenesis by metabolic rewiring of cancer cells (Chandel et al. 2000; Connor et al. 2005). On the other hand, ROS overexpression causes damage to lipids, nucleic acids, proteins, membranes, and organelles, leading to cell death by apoptosis (Halliwell 2011). ROS also induces apoptosis through mitochondrial translocation of p53 and by inducing the opening of the mitochondrial permeability transition pore (MPTP) through oxidative modifications in several components of the MPTP such as voltage-dependent anion channel, cyclophilin D, and adenine nucleotide translocase (Circu and Aw 2012; Pallepati and Averill-Bates 2010). Additionally, mitochondrial p53 inhibits Bcl-2 and Bcl-XL anti-apoptotic proteins, induces the oligomerization of Bax and Bak pro-apoptotic proteins, and forms a complex with cyclophilin D, leading to a release of apoptogenic factors to the cytosol. Furthermore, H2O2 promotes mitochondrial membrane hyperpolarization, which generates damage in the mitochondrial membrane potential and subsequent mitochondrial translocation of proapoptotic proteins such as Bad and Bax, as well as cytochrome C release from mitochondria to the cytosol (Yang et al. 2017). Low cytochrome C levels in the mitochondria will lead to disruption of the ETC, increasing ROS production (Circu and Aw 2010). Therefore, the ETC impacts several processes beyond energy balance, including the redox state, reactive oxygen species generation, signaling, mitochondrial membrane potential, and apoptosis (Bell et al. 2007, Chandel 2014, Chen et al. 2014, Di Lisa and Ziegler 2001, Pagliarini and Rutter 2013).
3.1 Electron transport chain and oxidative phosphorylation in glioblastoma
Mitochondrial ultrastructural and genetic dysfunction in gliomas have been linked to abnormalities in energy metabolism, marked by a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis (the “Warburg effect”). In this sense, ultrastructural level morphological alterations have been observed in the mitochondria of some brain tumors (Connor et al. 2005, Halliwell 2011). Structural changes to the mitochondria, such as swelling (disarrangement of cristae), partial and total cristolysis, and altered fission and fusion cycles, result in a heterogeneous group of mitochondria in several grades of glioma, suggesting that oxidative phosphorylation is highly inhibited (Arismendi-Morillo 2011). Feichtinger and colleagues reported a low copy number and mutations in mitochondrial DNA in GBM tissue compared with normal human brain samples (Feichtinger et al. 2014), which is related to a reduced but functional oxidative metabolism (Meixensberger et al. 1995). Additionally, cancer cells deficient in OXPHOS due to mitochondrial DNA depletion cannot form tumors unless they acquire functional mitochondrial DNA from the host stroma, suggesting that functional OXPHOS is essential for tumor formation (Tan et al. 2015). Dickinsol and coworkers reported that a gradual depletion in mtDNA content in human glioma HSR-GBM1 cells resulted in a phenotype unable to recover in vitro, while injection of HSR-GBM1 cells into immunocompromised mice resulted in a delay of tumor formation and restoration of mitochondrial function, relative to the degree of mtDNA copy depletion (Dickinson et al. 2013).
On the other hand, it has been signaled that glioma cells have a high OXPHOS to promote tumor survival (Janiszewska et al. 2012). Margareto and colleagues reported a significant overexpression of a higher number of genes involved in the OXPHOS process in glioblastoma tumors compared to low-grade glioma tumors (Margareto et al. 2007). A multiomic study revealed a new subtype of GBM named mitochondrial GBM, which mainly contains oxidative cells showing higher activity in oxidative phosphorylation and a decrease in glycolysis (Garofano et al. 2021). Furthermore, mitochondrial GBM is associated with therapeutic vulnerabilities to OXPHOS inhibitors and radiation through the induction of cell death by ROS generation (Garofano et al. 2021). In this sense, chemoresistance to temozolomide in glioma cells is associated with higher efficiency in mitochondrial coupling and low ROS production, particularly in O2 •− via the electron transport chain, demonstrating that modulation in mitochondrial functions and perturbation in redox status can be a strategy for sensitizing glioblastoma cells to therapeutic strategies (Oliva et al. 2011). The inhibition of complex I of ETC with rotenone and metformin sensitizes radioresistant glioma cells to X-ray radiation through ROS production and downregulation in mRNA of Complex I subunits such as NDUFAF2, NDUFA11, NDUFA13, NDUFB7, NDUFB1, NDUFC2-KCTD14, and PET117 (Gao et al. 2020).
On the other hand, it has been suggested that the survival of glioma cells is associated with altered biosynthetic requirements rather than cancer-linked mitochondrial damage (Oppermann et al. 2016). In this sense, glioblastoma cells show to be highly flexible in nutritional supply (Oppermann et al. 2016). Moreover, it has been demonstrated the activation of OXPHOS in glioma cell lines under nutrient deprivation and hypoxia to satisfy ATP requirements due to their capacity to switch from aerobic to anaerobic metabolism in response to specific environmental conditions, suggesting that mitochondria have a functional tricarboxylic acid cycle and respiratory complex as well as tightly coupled OXPHOS, given that pyruvate and lactate were able to rescue glioma cells grown under low glucose conditions (Griguer et al. 2005). It has been demonstrated that lactate and pyruvate produced by anaerobic glycolysis in hypoxic regions can be used as oxidative substrates in the adjacent region where oxygen supply is higher (Griguer et al. 2005). Additionally, Kim and coworkers reported that U87 glioma cells support their growth, migration, and cell invasion through glycolytic and oxidative metabolism (Kim et al. 2015). Inhibition of both glycolysis and OXPHOS with 2-deoxyglucose (2-DG) and oligomycin, respectively, suppressed synergistic cell migration, blocking glioblastoma tumorigenic phenotypes (Kennedy et al. 2013). The findings in glioblastoma mitochondrial complexes are detailed below.
3.1.1 Complex I
Complex I is composed of a group of flavin mononucleotides, four sulfur-iron centers, 10 ubiquinones, and phospholipids. It has 46 subunits; 39 of which are encoded by genes from the nucleus and seven from mitochondrial genes (Janssen et al. 2006). In this sense, a decrease in the expression of 23 proteins from complex I was observed in brain samples from glioblastoma patients (Deighton et al. 2014). However, the NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) subunit is overexpressed in both mRNA and protein, which correlates with short patient survival (Chen et al. 2021). Downregulation of the NDUFA4L2 gene in vitro and in vivo inhibits cell proliferation by blocking mitophagy and induces apoptosis in glioma cells (Chen et al. 2021). A mutation in the ND6 subunit encoded by mitochondrial DNA has been identified, which is associated with a hypoxia-sensitive phenotype in human glioblastoma cell lines M010b; this mutation does not block the synthesis of the ND6 protein but contributes to resistance to chemotherapeutic agents due to altered function and structure of Complex I (DeHaan et al. 2004). Yeung and colleagues reported that variants in coding regions of ND4 and ND6 are the cause of initiating the development of glioblastoma (Yeung et al. 2014). Also, it has been demonstrated that Complex I is involved in the radioresistance of glioma cells and the survival of glioma patients with chemo/radiotherapy due to an increase in the number of mitochondrial copies and the NDUFAF2, NDUFA13, NDUFA11, NDUFB7, NDUFC2, and NDUFB1 subunits of Complex I (Gao et al. 2020), whereas rotenone and metformin, both inhibitors of Complex I, increase the sensitization of glioma cells to radiation (Gao et al. 2020). Also, it has been observed that the inhibition of Complex I by vercipyrone has a cytotoxic effect on CRL2366 glioma cells defective in DNA repair mechanisms via inhibition of OXPHOS and depletion of ATP (Leiris et al. 2010). Bu and coworkers suggested that the response to DNA damage induces the activation of mitochondrial respiration to increase ATP production and deoxyribonucleoside triphosphate, which are necessary for effective DNA repair (Bu et al. 2019). Additionally, it has been demonstrated that Juglona (naphthoquinone) inhibits the activity of Complex I, increasing the superoxide anion and hydrogen peroxide levels, inducing anti-proliferative and anti-invasive effects on glioblastoma C6 cells (Sidlauskas et al. 2017). On the other hand, the fenofibrate cell line inhibits Complex I in turn and decreases the concentration of intracellular ATP, generating phosphorylation of AMPK, promoting the inhibition of mTOR and subsequently expression of autophagy in in vitro and in vivo models of human glioblastoma (Wilk et al. 2015).
3.1.2 Complex II
Complex II, or succinate dehydrogenase (SDH), consists of four subunits: SDHA, SDHB, SDHC, and SDHD, which are encoded in nuclear genes (Bardella et al. 2011). Although no SDH mutations have been reported in GBM, an increase in mRNA coding for SDH subunits in human GBM cells has been observed (Chinopoulos and Seyfried 2018). Glioma U87 stem cells are highly tumorigenic in vitro and in vivo compared to parental U87 cells due to a decrease in SDHB protein, which induces a defect in the activity of Complex II of the ETC, leading to an increment in glycolysis. Consequently, lower mitochondrial respiration, an increase in ROS formation, and stabilization of HIF-1α, which increase the sensitivity of glioma U87 stem cells to glycolytic inhibitors, have been observed (Zhou et al. 2011). The combination of Gamitrinib (a mitochondrial chaperone inhibitor) and panobinostat (a histone deacetylase (HDAC) inhibitor) induces a synergistic reduction in tumor volume of xenograft human glioblastoma cells, accompanied by apoptosis and reduced energy metabolism via suppression of the expression of Complex II protein, the reduction of the potential of the mitochondrial membrane, as well as the cytoplasmic release of cytochrome c, and the activation of caspase 9, subsequently leading to activation of caspases 3 and 7 (Nguyen et al. 2020; Wang et al. 2021).
3.1.3 Complex III
Complex III is made up of 11 protein subunits, one encoded by mitochondrial DNA, and 10 genes from nuclear DNA. This complex is called cytochrome c reductase, also known as the cytochrome b-c1 complex, and is constituted by a large set of membrane proteins that function as dimers Figure 2. Each monomer contains three groups: cytochrome (two b and one c1) and an iron-sulfur group (Covian and Trumpower 2008; Yu et al. 1999). It has been identified that 200 mutations in mitochondrial DNA from GBM cell lines, whereas 25 mutations were located in Complex III, affecting the electron transport chain (Lloyd et al. 2015). Glioma U251 cells resistant to temozolomide presented a reduction in mtDNA copy number and high mitochondrial heteroplasmy compared to parental glioma U251 cells. Consequently, a remodeling of the electron transport chain was observed, with a significant decrease in the activities of Complexes I and V, and activation in the activity of Complexes II, III, and IV (Oliva et al. 2010). Moreover, the inhibition of the activity of Complexes II, III, and IV induces susceptibility of glioma cells to TMZ by apoptosis (Oliva et al. 2010). Furthermore, similar alterations in electron transport chain complex activity induced by temozolomide are present in primary and recurrent biopsies of GBM patients (Oliva et al. 2010). Also, it has been observed that Mahanine alkaloid inhibits Complex III of the electron transport chain in glioma cells, promoting a decrease in the respiratory control index through electron leakage and thereby increasing ROS production. In turn, Mahanine activates the DNA damage response followed by Chk1 and Chk2 activation, which induce a cell cycle arrest in G0/G1 phase mediated by the downregulation of CDC25A phosphatase, cyclin D1, -D3, and CDK4, -6 (Bhattacharya et al. 2014).
3.1.4 Complex IV
Complex IV, or COX, is the last enzyme in the mitochondrial respiratory chain, which reduces oxygen to water. This complex is made up of 14 subunits embedded in the mitochondrial inner membrane; three subunits are encoded by mitochondrial DNA and 11 by nuclear DNA. Two of the core subunits of the COX1 and COX2 complex contain metal cofactors involved in electron transfer (Swaminathan and Gohil 2022). As in Complex III, 52 mutations were found in 12 samples from patients with glioblastoma in the somatic mitochondrial DNA of Complex IV (Soon et al. 2022). The expression of COX Subunit 5B (COX5B) in glioblastoma samples was studied by immunohistochemistry, and an increase of 77 % was found. This analysis showed that COX5B expression is significantly associated with the clinical status of the patient and not with tumor size (Ochiai et al. 1975). It has been observed that Complex IV, together with p53, modulates the survival or death cell mechanisms of glioma cells under hypoxia and decreased glucose conditions. When p53 is active, it inhibits glycolysis, increases OXPHOS, decreases ROS, and thus promotes cell survival by inducing the expression and activity of cytochrome c oxidase 2 (SCO2). On the contrary, the suppression of p53 increases glycolysis activity, lactate production, inhibits OXPHOS, and increases ROS production, leading to cell death by decreasing SCO2 expression and activity (Wanka et al. 2012). SCO2 assembles cytochrome c oxidase (COX2) into the COX complex (Matoba et al. 2006). Also, it has been demonstrated that the inhibition of cytochrome c oxidase by ADDA5 promotes an antineoplastic effect in temozolomide-resistant U251 cells. Tumor growth inhibition was observed in glioma xenograft mouse models treated with ADDA5 (Oliva et al. 2016). On the other hand, Erusalimsky and colleagues observed that the inhibition of cytochrome c oxidase with nitric oxide increases ROS production, which induces the activation of transcriptional factors such as NF-ĸB, NFR-2, and FOXO involved in the upregulation of cytoprotective genes, anti-apoptotic factors, and antioxidant defenses (Erusalimsky and Moncada 2007).
Besides, it has been studied how mitochondrial DNA participates in the initiation and maintenance of the tumor (Dickinson et al. 2013) and how ROS maintains the phenotype of the cancer cell (Raimondi et al. 2020). Bednarczyk and colleagues (2013) observed that Complex IV is functionally and structurally coupled with potassium channels regulated by Ca2+ of large mitochondrial conductance (mitoBKCa) in the glioblastoma U87 cell line. These types of channels are widely distributed in the plasma membrane of the cell, and it was discovered that there is a similar potassium channel in the inner membrane of the mitochondria (Siemen et al. 1999). The authors argue that this functional coupling of a complex COX voltage generator and one mitoBKCa heatsink could have a novel regulatory impact on mitochondrial electrochemical homeostasis, and therefore questions arise about the molecular mechanism, such as its functional role in this type of coupling in glioblastoma, and whether this coupling is involved in the resistance of this type of cancer to chemotherapy treatment (Bednarczyk et al. 2013).
Additionally, it has been observed that mitochondria can form mitochondrial supercomplexes (Nesci et al. 2021). These supercomplexes, or respirasomes, in the electron transport chain, depend on their organization and function on the protein cytochrome c oxidase subunit 7A2L (COX7A2L), which is involved in the assembly of supercomplex III2 to IV. COX7A2L accelerates the assembly of Complex III to the supercomplex and thus preserves the stability of individual complexes or also minimizes the production of ROS (Lobo-Jarne et al. 2018). COX7A2L expression increased fourfold after 48 h of nutritional stress in U87 glioma cells, changing glucose for galactose and stimulating mitochondrial energy metabolism. Also, COX7A2L expression increased after glioma cell exposure to oxidative stress with hydrogen peroxide. However, the organization of the mitochondrial transport chain or the formation of supercomplexes in glioblastoma U87 cells remains unaltered (Lobo-Jarne et al. 2018).
3.1.5 Complex V
The complex V is made up of two domains, F0 embedded in the inner membrane of the mitochondria, while F1 is in the mitochondrial matrix. It contains approximately 18–25 subunits, two encoded from mitochondrial DNA and the others from nuclear DNA (Nesci et al. 2020). It has been observed in samples of patients with glioblastoma that the ATP5F1 gene is overexpressed, which participates in the transport of protons (Margareto et al. 2007), as well as an increase in the expression of messenger RNA of the subunits ATP5A1 and ATP5B (α and β subunits of the F1 domain) (Nesci et al. 2020; Wang et al. 2021). In contrast, a decrease in ATP6 messenger RNA levels, which encodes the α subunit to allow the flow of protons, has been reported in some glioblastomas (Dmitrenko et al. 2005, Wang et al. 2021). The ATP content has also been studied in glioblastoma tumor cells of patients. Glioblastoma samples showed lower ATP concentrations compared to progenitor cells (Vlashi et al. 2011). Yin and colleagues reported that the combination of temozolomide and celecoxib on glioma cells decreases cell proliferation induces apoptotic cell death, and autophagy through down-regulation of mitochondrial transcription factor A (TFAM) and inhibition of I and V complexes (Yin et al. 2021). Additionally, Shi and coworkers demonstrated that suppression of the F0F1 ATP synthase activity would inhibit the growth of GBM spheroids (Shi et al. 2019). It has been observed that erucylphosphohomocholine, a derivative of alkylphosphocholines, induces apoptosis via mitochondria in U87 and U118 glioblastoma cells, suggesting that the F0 subunit of ATPase and proton exchange in the mitochondrial inner membrane participates in the generation of ROS, decrease in ATP. In consequence, there is an alteration in the transition pore of mitochondria and cytochrome c is released into the cytosol to activate caspase nine and induce apoptosis (Kugler et al. 2008; Veenman et al. 2010).
3.2 Targeting OXPHOS for glioblastoma therapy
It has been suggested that the balance between glycolysis and oxidative phosphorylation (OXPHOS) supports the survival of cancer cells. Therefore, a potential therapeutic strategy for glioma cells is to disrupt this balance by inhibiting OXPHOS (Kim et al. 2017). In this sense, the metabolic modulation by inhibition of glycolysis and OXPHOS overactivation in several glioma models through the inhibition of pyruvate dehydrogenase kinase 1 (PDHK1) by dichloroacetate (DCA) stimulates the reactivation at PDH and cell death in glioma cells (Kim et al. 2017). DCA together with radiation inhibits glycolysis, induces a cell cycle arrest in the G2/M phase, and increases ROS as well as increases DNA damage levels in glioblastoma cells resistant to radiotherapy (Shen et al. 2015). Furthermore, Duan and colleagues demonstrated that DCA inhibited cell proliferation and induced apoptosis via mitochondria by promoting ROS formation, decreasing the mitochondrial membrane potential, and showed an anti-angiogenic effect in biopsies of rat glioma brain (Duan et al. 2013). Additionally, Michelakis and coworkers reported that DCA in glioma cells induces apoptosis and suppressed cell proliferation and angiogenesis by promoting the activation of p53 and inhibition of HIF-1α, which cause an increase in mitochondrial respiration, ROS, and p21 with a decrease in the concentrations of proliferating cell nuclear antigen (PCNA), hexokinase 2, VEGF, and α-ketoglutarate dehydrogenase (Michelakis et al. 2010). Also, it has been observed that suppression of complex I by metformin together with 2-DG inhibited the formation and invasive capacity of GBM neurospheres in vitro and in vivo, suggesting that under the loss of the glycolytic pathway, glioma cells utilize OXPHOS for their survival, whereas the inhibition of complex I is cytotoxic for cancer cells (Kim et al. 2017).
Moreover, it has been demonstrated that rotenone (complex I inhibitor), antimycin (complex III inhibitor), and oligomycin A (complex V inhibitor) promote a decrease in proliferation and induce apoptosis via mitochondria on glioma stem-like cells (GSCs) about from 100-fold more potent than TMZ (Datta et al. 2021, Kuramoto et al. 2020). Furthermore, three Food and Drug Administration (FDA)-approved drugs such as pyrvinium pamoate, mitoxantrone, and trifluoperazine, also decrease GSC viability about 50 fold more effectively than TMZ; whereas pyrvinium pamoate, mitoxantrone induces apoptosis and trifluoperazine promotes necroptosis over apoptosis (Datta et al. 2021). Verteporfin, another drug approved by FDA, is a pro-apoptotic agent in glioma stem cells by reducing mitochondrial membrane potential and OXPHOS activity promotes a low in ATP production in a YAP and reactive oxygen species-independent manner (Kuramoto et al. 2020). Also, verteporfin inhibits growth in glioma cells by activating p38 MAPK, a pro-apoptotic protein, and inhibits the YAP pathway, which mediates Hippo signaling and PI3K/AKT, and the pluripotent marker Oct-4 (Al-Moujahed et al. 2017). These results suggest that the activity of mitochondrial ETC and OXPHOS are essential for GSC proliferation and survival in tumors, and the specific inhibition of OXPHOS by drugs in GSCs is important for the elimination of GSC (Kuramoto et al. 2020). On the other hand, it has been demonstrated that both rotenone and thenoyl trifluoroacetone (TTFA, complex II inhibitor) induce ROS, which mediates autophagic cell death in glioblastoma U87 cells by inducing the conversion of LC3-I to LC3-II and up-regulates the expression of Beclin 1 and Atg5 (Chen et al. 2007). Also, it has been observed that SH-4-54, a compound based on salicylic acid (STAT-3 inhibitor) induces OXPHOS dysfunction and apoptosis in TMZ resistant glioma cells through inhibition of the phosphorylation at Tyr705 STAT3 via GRIM-19 promoting mitochondrial translocation of STAT3, which might negatively regulate expression of mtDNA-encoded oxidation respiratory genes such as complex I, III and IV through TFAM, leading to mitochondrial dysfunction and apoptotic pathway by causing significant opening of the MPTP, increased generation of ROS, decreased basal respiration, ATP production, maximal respiration, and spare respiratory capacity. Furthermore, these changes were accompanied by decreased oxidative phosphorylation activities of complexes I, III, and IV consistent with the respiration rates (Cui et al. 2020). Imipridones in combination with HDAC1/2 inhibitors induce a synergistic activation of apoptosis in the GBM model mediated by the activation of mitochondrial caseinolytic protease (CLPP) (Nguyen et al. 2022). It has been demonstrated that CLPP induces degradation of proteins that form the respiratory complexes, such as NDUFB8 and NDUFA12 (complex I), SDHA, SDHB (complex II), UQCRC2 (complex III) as well as proteins related to IV and V complexes and thereby diminishes cellular respiration and ATP production (Ishizawa et al. 2019). On the other hand, Gboxin, a cationic lipophilic molecule, accumulates in the mitochondrial matrix driven by the mitochondrial inner transmembrane potential (ΔΨm) leading to inhibition of F0F1 ATP synthase activity and causing a reduction of membrane potential, a depletion in the O2 consumption rate, and AMPK activation in glioma cells; also reduced the tumoral growth of human glioblastoma xenografts in mice (Shi et al. 2019).
4 Conclusions
TCA dysregulation is a key factor in the malignity of glioblastoma. The enzymes involved in this metabolic pathway and reviewed in this manuscript, could be altered, and participate in the metabolic adaptation to support the glioblastoma development and malignity, particularly in under nutrient-limiting conditions. Moreover, the metabolites derived from each step of the TCA also participate as catabolic and anabolic intermediates. However, new therapeutic strategies pointed to the TCA enzymes, or their metabolites emerged as alternative to drain the energy supply and viability to glioma cells, being a potential treatment.
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Research ethics: Not applicable.
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Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: The authors state no conflict of interest.
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Research funding: None declared.
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Data availability: Not applicable.
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Articles in the same Issue
- Frontmatter
- Amphetamine and methylphenidate potential on the recovery from stroke and traumatic brain injury: a review
- Insights on cognitive reorganization after hemispherectomy in Rasmussen’s encephalitis. A narrative review
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Articles in the same Issue
- Frontmatter
- Amphetamine and methylphenidate potential on the recovery from stroke and traumatic brain injury: a review
- Insights on cognitive reorganization after hemispherectomy in Rasmussen’s encephalitis. A narrative review
- Task-based EEG and fMRI paradigms in a multimodal clinical diagnostic framework for disorders of consciousness
- The impact of genetic factors on the response to migraine therapy
- Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma
