Mitochondrial thermogenesis in cancer cells
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Xiaoyue Zhang
Abstract
Organisms, following the laws of thermodynamics, require a constant supply of energy to maintain their daily activities. Catabolism, a controlled degradation process, not only releases Gibbs free energy and regenerates ATP but also dissipates excess energy as heat. Despite this, the molecular mechanisms governing heat production within cells remain elusive, and intracellular temperature remains a topic of inquiry. Numerous efforts have been made to develop thermosensors such as quantum dot-based nanoparticles, gold nanoclusters, and thermoresponsive probes, significantly advancing our ability to study intracellular temperature. Mitochondria, significant energy providers in the form of ATP, are strongly implicated in thermogenesis. In addition to energy production, mitochondria are pivotal in various signaling pathways, including calcium homeostasis, cellular redox state, and apoptosis. Simultaneously, they are central to various pathogenic processes, including cancer development. This dual role underscores the potential involvement of mitochondria in thermogenesis across cancer cells. Understanding this intersection is critical, as unraveling the mechanisms of mitochondrial thermogenesis in cancer cells may pave the way for innovative, targeted cancer therapies.
Introduction
The laws of thermodynamics play a crucial role in understanding how energy, heat, and life are interconnected in highly organized systems. For organisms to function daily, they require a significant input of high-level energy [1]. Catabolism, a controlled degradation process of molecules, releases energy in the form of Gibbs free energy and regenerates ATP, which is essential to power cellular functions. The energy that remains unused during this process is transformed into heat, causing a local increase in temperature [1], [2], [3].
Temperature, a fundamental factor, greatly influences various biological processes such as biochemical reactions, gene expression, and cell functions [2, 4], [5], [6], [7], [8], [9]. Despite its importance, the specific molecular mechanisms cells use to generate and utilize heat remain unclear [6]. This uncertainty has led to a growing interest in techniques that allow precise measurement of intracellular temperature, especially with optical and remote readability [4, 5, 10]. Utilizing fluorescent probes and their temperature-dependent properties like emission intensity, emission lifetime, or emission wavelength, researchers have developed methods to visualize temperature variations in samples both in vitro and in vivo [2, 4, 11, 12].
Over the years, researchers have explored the intracellular temperature heterogeneity using various methods. For example, they have employed quantum dot-based nanoparticles to quantify intracellular temperature distribution in neuronal cell cytoplasm [2]. Gold nanoclusters, sensitive to temperature, have been used to detect temperature differences in human cervical cancer cell lines (HeLa cells) [7]. The development of a fluorescent polymeric thermometer (FPT) with high spatial and temperature resolution enabled thermal imaging of living cells and revealed that cell nuclei tend to have higher temperatures than the cytoplasm [10]. The same group optimized the FPT to bypass microinjection, and the results further collaborated their previous findings [8]. Nakano et al. combined two temperature-sensitive fluorescent proteins, to overcome the shortcomings in temperature range and response time in previous thermometers. Their measurements indicated a higher ratio value in the nucleus region, and an estimated difference between the nucleus and the cytosol [9].
Furthermore, researchers are increasingly focusing on evaluating thermogenesis in individual cells. Techniques using genetically encoded green fluorescent protein-based thermosensors have been applied to target subcellular organelles, uncovering thermogenesis heterogeneity in mitochondria of HeLa cells [13]. Using quantum dots for intracellular temperature sensing, Yang et al. reported the first experimental evidence for the inhomogeneous local temperature progression in single living cells [3]. A thermoresponsive probe targeting mitochondria was tested in murine bladder cancer cells, and revealed a relatively high temperature [14].
In this review, we begin by exploring the physiological aspects of mitochondria, delving into their role in thermogenesis. We discuss the latest investigative designs and techniques, shedding light on potential mechanisms within mitochondria that contribute to intracellular temperature heterogeneity, especially in cancer cells. Additionally, we examine carcinogenic factors stemming from mitochondria. By combining this knowledge with targeted therapy, we envision the development of novel, more effective strategies for cancer treatment.
Mitochondria and thermogenesis
The structure and function of mitochondria
The mitochondrion is divided into four compartments by two membranes: the outer membrane, the intermembrane space, the inner membrane, and the matrix [15]. The primary function of mitochondria in eukaryotic cells is to produce energy through oxidative phosphorylation (OXPHOS) [16], [17], [18], [19]. These substrates are catabolized to acetyl coenzyme A (acetyl-CoA) after processes such as glycolysis, beta oxidation, or enzymatic conversions, and then enter the tricarboxylic acid (TCA) cycle [16, 18]. The electron transport chain (ETC) located on the inner mitochondrial membrane (IMM) consists of a series of protein complexes [20]. Cofactors like nicotinamide adenine dinucleotide (NADH) and flavine adenine dinucleotide (FADH2) carry electrons from glycolysis, fatty acid oxidation, and the TCA cycle to the ETC, driving the pumping of protons from the matrix into the intermembrane space [16, 18, 21, 22]. This translocation of protons generates a potential difference within the IMM, which eventually facilitates ATP synthesis [18, 20], [21], [22].
In addition to energy production, mitochondria are pivotal in various signaling pathways, including calcium homeostasis, cellular redox state, and apoptosis [3, 17, 18, 23]. They communicate with the cytosol primarily via calcium signaling between the cytosol and matrix, thus maintaining the balance between cellular energy demands and production [18]. Calcium ions (Ca2+), a vital intracellular second messenger, enter the intermembrane space of the mitochondria before reaching the matrix, influencing ATP synthesis. The endoplasmic reticulum (ER) stores the majority of intracellular Ca2+, releasing it into the cytosol when triggered, thereby increasing cytosolic Ca2+ concentration [19]. Elevated Ca2+ levels induce microdomains of high Ca2+ concentrations within the outer mitochondrial membrane, activating the mitochondrial calcium uniporter (MCU) and allowing Ca2+ uptake [17, 19].
If a biological system is altered due to changes in either the level of certain reactive oxygen species (ROS) or the redox state of a responsive group, redox signaling will be generated [24]. When mitochondria employ oxygen during OXPHOS to synthesize ATP, ROS are formed as a result of redox reactions from one electron reduction of oxygen [25, 26]. Normally, about 1–2 % of oxygen consumption in mitochondria results in ROS production [27, 28]. Although ROS are known to potentially cause oxidative damage to cellular components, they are also vital in many signaling pathways [26]. Initially produced as superoxide (O2˙−) by the ETC and other enzymes, mitochondrial ROS are predominantly converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD) in the matrix [24], [25], [26, 28]. The more stable H2O2 can diffuse across membranes and oxidize thiol residues on proteins, functioning as a redox signal in the crosstalk between the mitochondria and the rest of the cell [24], [25], [26]. Alternatively, mitochondria-generated H2O2 can be converted by tetrahydrobiopterin in the glutathione redox system, react with O2·−, or generate highly reactive hydroxyl radicals (·OH) in the presence of transition metals [28].
Apoptosis, a distinct form of cell death both morphologically and biochemically, is initiated by various stimuli [29]. Two main cascades lead to apoptosis: the extrinsic pathway and the intrinsic pathway. In the extrinsic pathway, cell-membrane bound death receptors, belonging to the tumor necrosis factor superfamily and having a homologous death domain, attach to Fas-associated death domain, forming a death-inducing signal complex and activating a caspase cascade [29, 30]. On the other hand, mitochondria-initiated apoptosis is usually activated by cell-internal stimuli such as ROS and is regulated by pro-apoptotic proteins belonging to the B-cell lymphoma-2 (Bcl-2) family [29], [30], [31]. Members of the Bcl-2 family regulate mitochondrial outer membrane permeabilization, releasing mitochondrial intermembrane space proteins and facilitating caspase activation [29, 31].
The origin and studies of mitochondrial thermogenesis
Thermogenesis is closely linked to oxidative metabolism and is under the control of mitochondria. Mechanisms of thermogenesis encompass both increased energy utilization and decreased energy utilization efficiency [32]. Catabolism of carbon-containing molecules and ATP hydrolysis occur in various cell compartments, including the cytoplasm, mitochondria, lysosomes, and peroxisomes. However, mitochondria are the primary contributors to cellular thermogenesis [3, 32]. Due to the inherent inefficiency of mitochondrial ATP synthesis, a portion of the respiratory energy is dissipated as heat [32, 33]. Mitochondria of tissue like brown fat are even specialized in producing heat. In the process of mitochondrial ATP production, the membrane potential (ΔΨ) primarily consists of voltage across the inner mitochondrial membrane (IMM). When uncoupling proteins (UCPs) disrupt the coupling between H+ flows and ATP synthase on the electron transport chain (ETC), H+ is passed down ΔΨ, but no ATP is generated [33]. Leakage occurs through various pathways, including the adenine nucleotide translocase (ANT) as an intrinsic and regulated function [1]. However, H+ leak is not the only cause of mitochondrial uncoupling; increasing the conductance of the IMM for any ion will lead to the same condition. This includes the mitochondrial calcium uniporter, potassium channels, and the permeability transition pore (PTP) [33].
Mammals possess two types of fat tissues: brown adipose tissue (BAT) and white adipose tissue (WAT). Within BAT, free fatty acids are oxidized, serving as a major energy source for BAT thermogenesis [34]. Mitochondrial protein uncoupling protein 1 (UCP1) is primarily responsible for BAT thermogenesis, expressed in brown adipocytes [33, 34]. Chronic adrenergic stimulation induces the formation of UCP1-expressing brown-like adipocytes in WAT, referred to as “beige adipocytes.” These beige adipocytes exhibit similar thermogenic UCP1 properties to brown adipocytes [34]. Conversely, Jung et al. applied an antiretroviral drug, dolutegravir (DTG), to a virus-free mouse model as well as human and murine cell cultures. As a result, DTG was found to induce UCP1 expression inhibition and disrupt thermogenesis in brown/beige adipocytes [35].
Additionally, UCP2-5 proteins have been identified in mammalian tissues, although their functions remain incompletely understood [21, 36, 37]. UCP2, expressed widely, plays roles that are still conflictingly suggested, such as attenuating mitochondrial ROS production and defending against oxidative stress. It may also modulate mitochondrial substrate routing through metabolite transport [21, 38], [39], [40]. UCP3, acting as a mediator in heart and skeletal muscle, regulates thermogenesis and could be involved in thermal homeostasis in vivo [36, 37].
Apart from natural physiological processes, chemical compounds can also uncouple mitochondria. These compounds function as protonophores, directly uncoupling ATP production by transporting protons into the matrix, or indirectly through proteins. Classic uncouplers like carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) and its analog carbonyl cyanide m-chlorophenylhydrazone (CCCP) have been extensively studied [21]. They are weakly acidic and bulky hydrophobic moieties that can traverse biological membranes in both neutral and charged states [21, 37].
In the context of ionophores, uncoupling occurs through the combination of a uniporter and an electroneutral antiporter, or the combination of an antiporter and a uniporter carrier protein of the membrane [37]. For instance, a Ca2+ ionophore facilitates Ca2+ translocation across the membrane during ATP cleavage without accumulating in the vesicle’s lumen. ATP hydrolysis energy then dissipates as heat [41]. Ionomycin, an ionophore, vastly increases the permeability of cellular and intracellular membranes to Ca2+ [42]. Activities of K+ channels and electrogenic transporters embedded in the IMM can also induce uncoupling and subsequent heat production [36].
Over the years, several research methodologies have been developed to measure mitochondrial temperature and gain a better understanding of mitochondrial thermogenesis. A recent study designed a diamond thermometer to measure the temperature of isolated mouse brain mitochondria. Application of the mitochondrial uncoupler CCCP resulted in a temperature increase of 4–22 °C above the ambient temperature, with an absolute maximum of 45 °C [43].
Other studies directly evaluate mitochondrial thermogenesis without isolating the organelles. Qiao et al. synthesized a fluorescent probe with a thermally sensitive polymer for temperature and ATP sensing of mitochondria in HeLa cells. After incubation with FCCP, they observed an initial temperature increase from approximately 32.6 °C–35.0 °C, accompanied by a simultaneous 75 % decrease in ATP [44]. Using high-density surface modifications, upconversion nanoparticles (UCNPs) were employed to accumulate in specific organelles in living cells. Treatment of HeLa cells with FCCP resulted in a significant increase of ∼3–7 °C in mitochondrial temperature within the first 10 min [45]. Alternatively, Ca2+ shock has often been employed to investigate the thermogenic process of mitochondria. After the engagement of FCCP, Qiao et al. further tested an ionomycin calcium complex, demonstrating similar results with ATP decreasing and temperature increasing [44]. UCNPs also detected an increase of ∼2–3 °C upon treatment with ionomycin calcium salt [45].
Mitochondria in cancer
Mitochondria in carcinogenesis
Mitochondria are highly dynamic organelles, continually changing their shape and size through fission and fusion processes [23, 46]. A delicate balance between fission, fusion, mitochondrial biogenesis, and mitophagy maintains mitochondrial functions [22]. This balance regulates mitochondrial structure, metabolism, and population during normal turnover and under stress [47]. Cells respond to varying metabolic needs, inducing mitochondrial biogenesis and fusion when demand increases, or removing excess mitochondria through fission and mitophagy otherwise [22].
The hallmarks of cancer involve various alterations at the cellular and molecular levels. Disorders in mitochondrial dynamics are associated with these mechanisms in many cancers [48], [49], [50]. The balance of mitochondrial fission and fusion is mediated by several key regulators. For instance, the mitochondrial fusion protein mitofusin-1 (MFN1) was found to shift the balance of mitochondrial dynamics from fission to fusion and counteract hepatocellular carcinoma (HCC) malignancy. However, MFN1 is a significantly downregulated gene in mitochondrial dynamics related to HCC metastasis and poor prognosis [50]. Additionally, oncogenic KRAS contributes to mitochondrial fragmentation in mouse models and patient-derived samples of pancreatic ductal adenocarcinoma (PDAC). Conversely, the suppression of mitochondrial fission in PDAC leads to mitophagy and mitochondrial loss, subsequently reducing OXHPOS and tumor growth [51].
Mitochondrial DNA (mtDNA) encodes 13 OXPHOS proteins necessary for proper functioning, along with 22 tRNAs and 2 rRNAs essential for accurate translation [20, 28, 52]. While all the subunits of ETC complex II are encoded by nuclear DNA (nDNA), the subunits of the remaining complexes are encoded by both nDNA and mtDNA [28]. mtDNA is highly susceptible to mutations, leading to OXPHOS disruption, increased ROS production, and mtDNA damage [20]. As multiple copies of mtDNA reside in individual cells, mutant and wild-type mtDNA can co-exist in heteroplasmy or homoplasmy when all the copies are the same [53]. Failed coordination of fission and fusion events impairs mitochondrial dynamics, potentially triggering inflammation via mtDNA unloading [31].
Cancer cells exhibit an aberrant redox balance and altered stress adaptation compared to normal cells. Enhanced ROS production coexists with elevated expression of the intracellular antioxidant system in cancer cells in vitro and in vivo. Given that an imbalanced redox homeostasis makes cells more susceptible to apoptosis induced by oxidative stress, ROS-generating drugs are being explored for their potential to disrupt mitochondrial functions and initiate apoptosis [54].
Regarding the induction of apoptosis and differentiation of preadipocytes by an antioxidative polyphenol xanthohumol (XN), a group investigated the specifics of XN-induced ROS formation. They identified mitochondria as the source of the rapid increase of O2˙− in malignant prostate cancer cell lines due to XN’s inhibitory potential on mitochondrial ETC complexes I to III [54]. Similarly, benzyl isothiocyanate (BITC) causes inhibitory effects on complex III, inducing ROS generation and apoptosis in human breast cancer cells [55]. This direction could also be applied in photodynamic therapy for cancer treatment. Yu et al. constructed a near-infrared triggered photosensitizer based on titanium oxide-coated UCNPs to target mitochondria, activate local ROS burst, and initiate the apoptotic pathway [56].
During early carcinogenesis, cells experience a hypoxic microenvironment, prompting them to initially rely on glycolysis for energy production, providing a survival advantage [57]. However, mitochondrial dysfunction can lead to persistent glycolysis even in aerobic conditions, a phenomenon known as the Warburg effect [57, 58]. Energy production through the OXPHOS pathway may not provide sufficient metabolites favoring cancer growth [59]. Positron emission tomography (PET) has confirmed the correlation of malignant tumors with increased glucose uptake and metabolism [57]. Since OXPHOS is essential for mediating cell death, cells that cannot perform OXPHOS and instead rely on glycolysis develop an apoptotic-resistant phenotype. Tumors show lower cellular expression levels of the β-subunit of the H+-ATP synthase compared to their normal counterparts. The progression of colon cancer is influenced by energetic metabolism shifts in mitochondria [60]. Nonetheless, OXPHOS can also be upregulated in some cancer cells for tumorigenic purposes. In MCF-7 breast cancer cell lines, 80 % of ATP is produced through oxidative metabolism [61]. Similarly, metastasis-associated antigen 1 is associated with elevated ATP production by ATP synthase in colorectal cancer cells [62].
Conversely, the glycolytic phenotype can be altered by enhancing OXPHOS and suppressing glycolysis. Pyruvate dehydrogenase (PDH) controls the metabolic routes of glucose. Dichloroacetate (DCA), an inhibitor of PDH kinase (PDK), induces mitochondrial depolarization, facilitating apoptosis and hindering tumor growth [57]. Furthermore, mitochondrial functions can be upregulated by suppressing glycolysis, a process reported to dramatically alter mitochondrial morphology [58].
From a genetic perspective, each cell contains multiple copies of mitochondria, and each mitochondrion typically holds 2–10 copies of the mitochondrial genome. Under normal physiological conditions, the amount of mtDNA remains relatively stable [63]. However, alterations in mtDNA have been reported to be frequent in many types of human cancer [53, 63], [64], [65], [66]. The D-loop, a non-coding region in mtDNA, acts as a promoter and contains essential transcription and replication elements. The D-loop region is a hotspot for mtDNA alterations. When the same mutation is observed in both cancer and normal tissue, it is considered a polymorphism [67]. Some germline polymorphisms in the D-loop region have been suggested to be associated with a higher risk of malignancies. A study on high-grade serous ovarian cancer (HGSOC) demonstrated a connection between the metabolic shift in tumor cells and heteroplasmic pathogenic somatic mtDNA mutations, with 62.5 % of samples harboring such mutations [64]. In stage I breast cancer, mtDNA content in whole blood was found to be depleted, essentially preventing apoptosis and promoting the production of cancer-related proteins [68]. Elevated mtDNA content was detected in the saliva of head and neck squamous cell carcinoma (HNSC) patients, potentially serving as a compensatory response to the decline in respiration [65]. Sun et al. demonstrated that an increased mtDNA copy number promotes cell survival and apoptosis resistance in the microsatellite-stable type of colorectal cancer [66].
Additionally, mtDNA mutations have been identified in prostate cancer, and deregulated mitochondrial metabolism could contribute to prostate carcinogenesis. Grupp et al. performed immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. The results revealed that cancer cells contained significantly more mitochondria compared to normal prostate epithelial cells. Furthermore, the increase in mitochondria content paralleled the progression of tumor grade and stage, indicating the potential role of mitochondria in cancer development [69].
Possible mitochondrial thermogenesis mechanisms
Given that the temperature of mitochondria is reported to be higher in cancer cells [70], we now explore potential molecular mechanisms involved in this thermogenic process. These mechanisms can be categorized into two main groups: mitochondrial uncoupling and enhanced OXPHOS (Figure 1).
![Figure 1:
Mitochondrial thermogenesis mechanisms in cancer cell [71]. I-V, ETC complexes I-V; CoQ, coenzyme Q; Cyt c, cytochrome c; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane.](/document/doi/10.1515/oncologie-2023-0298/asset/graphic/j_oncologie-2023-0298_fig_001.jpg)
Mitochondrial thermogenesis mechanisms in cancer cell [71]. I-V, ETC complexes I-V; CoQ, coenzyme Q; Cyt c, cytochrome c; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane.
Uncoupling proteins
The phenomenon of mitochondrial uncoupling, where the normal tight coupling between electron transport and ATP synthesis is disrupted, has been linked to a decrease in the expression of UCP2 in oocytes. The depletion of UCP2 can also lead to mitochondrial uncoupling [39]. This effect is likely compensated by another mechanism involving the adenine nucleotide transporter. In diabetic kidneys, knocking down UCP2 has been shown to elevate mitochondrial uncoupling [72].
In the context of cancer, a significant reduction in UCP2 expression has been observed in grade 1 and 2 tumor cells in primary breast cancer cell lines [40]. Studies have demonstrated that metabolic reprogramming induced by UCP2 can reduce cancer cell proliferation both in lab settings (in vitro) and in live organisms (in vivo) [38]. For example, experiments involving knockout mice have shown that invalidating UCP2 can increase the initiation of colon tumorigenesis [73]. Mutant p53 proteins, often associated with promoting cancer growth, are linked to the downregulation of the proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)/UCP2 axis [74]. Moreover, suppressing UCP2 might activate the AKT/mTOR pathway due to increased production of ROS [75]. In contrast, increasing UCP2 levels has been found to induce metabolic reprogramming and suppress the growth of rectal cancer in mice [59].
In addition to UCP2, there are other UCPs that play roles in cancer cells. For example, UCP1 is significantly overexpressed in squamous cancer cells, while UCP3 expression is enhanced in large-cell carcinomas [76]. Human renal cell carcinoma specimens often show upregulation of UCP3 and downregulation of UCP1 [77]. High expression of UCP1 is correlated with an increased rate of thermogenesis in breast cancer patients, suggesting its potential role in cancer metabolism [78]. Breast cancer cells have shown a UCP1-mediated uncoupling characterized by the depolarization of the mitochondrial membrane potential, displaying metabolic features similar to brown adipocytes, including increased glucose metabolism, mitochondrial proton leak, and mitochondrial respiration [79].
Respiration rate
Enhanced respiration might have been a factor in mitochondrial thermogenesis in cancer cells. While “aerobic glycolysis” is a well-known energy production process in many cancer cells, it is important to note that mitochondrial respiration remains a critical aspect of bioenergetics [80]. The respiratory activity of breast and colorectal cancers significantly differs from that of normal adjacent tissues, resembling the respiratory rates of rat skeletal muscles [81]. Similarly, non-small-cell lung cancer (NSCLC) cells exhibit heightened oxygen consumption and mitochondrial respiration compared to normal nonmalignant cells. These NSCLC cells also display increased heme synthesis, uptake, and incorporation into oxygen-utilizing hemoproteins. Heme, being vital for the entire process of oxygen metabolism, likely underpins the intensified oxygen consumption observed in these cancer cells [80]. Furthermore, enhanced mitochondrial OXPHOS and biogenesis in circulating cancer cells have been linked to the upregulation of PGC-1α expression. Conversely, the suppression of PGC-1α has a direct negative impact on ATP-coupled respiration and the efficiency of the ETC [82].
Mitochondria remodeling
In ovarian cancer tissues, there is an observed increase in the number of mitochondria and mitochondrial biogenesis, characterized by elevated expression of key regulators like PGC-1α and mitochondrial transcription factor A (TFAM). PGC-1α, a master regulator of mitochondrial biogenesis, enhances TFAM expression, promoting the transcription and translation of mitochondrial DNA [83]. Hirpara et al. established cell line models resistant to targeted therapies, showing significantly heightened mitochondrial oxygen consumption [OCR], indicative of enhanced mitochondrial OXPHOS. This switch is linked to increased mitochondrial DNA content and mass, corroborated by upregulated PGC-1α and TFAM expression [84].
Fascin, a protein crucial for bundling actin, is associated with pro-metastatic processes and is upregulated in NSCLC cases. Fascin not only modulates cell-matrix adhesion, interactions, and migration but also contributes to metabolic stress resistance and heightened mitochondrial OXPHOS in NSCLC cells [85, 86].
Another mechanism involves naïve adipocytes, which release extracellular vesicles (EV) containing biomolecules to distant cells. These vesicles carry protein machinery and fatty acid substrates that, upon uptake by melanoma cells, increase fatty acid oxidation, promoting tumor migration and invasion. Adipocyte proteins related to mitochondrial respiration and ATP production are also internalized by melanomas during this process [87].
In an alternative tumorigenesis model, epithelial cancer cells induce the Warburg effect in neighboring stromal fibroblasts. This leads to lactate and pyruvate production by fibroblasts, which are then taken up by cancer cells as substrates for their mitochondrial TCA cycle, promoting OXPHOS. Termed the “Reverse Warburg Effect,” this process effectively converts stromal cells into an energy source for cancer cells [88]. The co-culturing of human lung cancer cell line A549 and human lung fibroblasts demonstrated a reduction of glucose uptake in cancer cells, as well as an increment of lactate release in the fibroblasts [89]. Similar patterns were also observed in the co-culturing of murine lung fibroblasts and murine lung cancer cell line KLN205, which further supported the reverse Warburg effect model [88, 89].
Metastasis
A captivating study delved into the adaptation of two isogenic breast cancer cell lines: 4T1 and 67NR, under metabolic and environmental stress. The comparison revealed substantial differences. Metastatic 4T1 cells displayed a significantly higher basal respiration rate, approximately 2.3-fold, and ATP production, around 2.2-fold, compared to the non-metastatic 67NR cells. This highlights a potential correlation between mitochondrial OXPHOS and the metastatic potential of these breast cancer cells. This correlation was further substantiated by studying two additional cell lines from the same isogenic breast cancer family. The synthesis rate of 13C labeled glutamate, a participant in the TCA cycle, was notably higher in 4T1 cells than in 67NR cells. This trend was consistent across other molecules related to the TCA cycle, further emphasizing the potential link between mitochondrial OXPHOS and the metastatic behavior of breast cancer cells [90].
Heme levels
The major facilitator superfamily domain containing 7C (MFSD7C) has been identified as a pivotal player in shifting ATP synthesis to thermogenesis, as documented in a previous study [91]. Another essential aspect of cellular dynamics involves sarcoendoplasmic reticulum Ca2+-ATPase (SERCA), crucial for maintaining the dynamic equilibrium of endoplasmic reticulum (ER) calcium homeostasis. SERCA proteins, encoded by three genes, include SERCA2b, which is a widely expressed isoform [92]. Initially, MFSD7C interacts with components of the ETC and SERCA2b, facilitating SERCA2b degradation while maintaining coupled mitochondrial respiration. However, this situation can change based on heme levels within the cell. When heme levels rise, heme molecules bind to the N-terminal domain (NTD) of MFSD7C. This binding stabilizes SERCA2b and uncouples mitochondrial respiration, ultimately inducing thermogenesis [91]. Notably, NSCLC cells have been observed to exhibit an increase in heme synthesis, uptake, and integration into oxygen-utilizing hemoproteins. Furthermore, several significant hemoproteins, such as cytoglobin, cytochrome c, cytochrome P450 (key metabolic enzymes [93]), and cyclooxygenase-2 (COX-2), known for their involvement in oxygen transport and utilization, were found to be upregulated in NSCLC cells [80]. Therefore, it is plausible to suggest that elevated heme levels in NSCLC cells enable the NTD of MFSD7C to interact with heme, leading to the uncoupling of mitochondrial respiration and the initiation of thermogenesis. This insight opens up promising directions for future investigations, potentially extending to other cancer cell lines.
Sirtuin-3 (SIRT3)
SIRT3 is a crucial mitochondrial deacetylase known for its role in modulating enzymes central to metabolism and activating oxidative pathways [94]. Hypoxia-inducible factor (HIF) is a prominent transcription factor responsible for cellular responses to low oxygen levels [94, 95]. HIF exists as a heterodimer, consisting of the oxygen-regulated and growth-factor-sensitive α subunit and the constitutively expressed β subunit. Among the α subunits, HIF1α, HIF2α, and HIF3α, along with the β subunit HIF1β, make up the HIF isoforms [95].
In hypoxic conditions, HIF1α promotes glycolysis and lactate production while repressing mitochondrial ETC activity [94, 95]. SIRT3 plays a crucial role in mediating glycolysis by regulating the stability and activity of HIF1α. Additionally, SIRT3 has been found to repress the Warburg effect in human breast cancer cell lines, indicating a shift towards OXPHOS and thermogenesis [94]. Despite being deleted in several human cancers like breast and ovarian cancers, SIRT3 expression is upregulated in human NSCLC tissues and even more in squamous cell carcinoma [94, 96]. Furthermore, SIRT3 has been identified as an activator upstream of the Akt signaling pathway in NSCLC [96]. In colorectal cancer (CRC), SIRT3 regulates mitochondrial function by mediating mitochondrial fission, with the Akt/PTEN pathway being involved. Enhanced SIRT3 expression in CRC leads to sustained migratory response and survival [97].
SIRT3 interacts with nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) to promote mitochondrial functions in the NSCLC cell line A549. This interaction not only impacts mitochondrial functions but also influences mitotic entry, cell growth, proliferation, and inhibits apoptosis in A549 cells [98]. In cervical cancer, SIRT3 plays an oncogenic role, and high expression levels of SIRT3 in patients with cervical cancer are associated with lymph node metastasis. The study also demonstrated that SIRT3 contributes to fatty acid synthesis in cervical squamous cell carcinoma (CSCC) cells by upregulating acetyl-CoA carboxylase 1 (ACC-1), making it a pivotal regulator of lipid metabolism [99].
HIF related
Cytochrome C oxidase (COX) staining levels showed a significant increase in cancer cells within HIF2α-tumor xenograft samples in situ, indicating that HIF2α promotes OXPHOS. HIF2α plays a crucial role in maintaining proper mitochondrial functions, and it is noteworthy that HIF2α is a target gene of PGC1α. In a xenograft model of clear-cell renal carcinoma, increased tumor growth rates were observed when HIF2α expression was upregulated. This upregulation was accompanied by an increase in the expression of key mitochondrial proteins and a decrease in the expression of the Krebs cycle inhibitor, along with a reduction in intra-tumoral lactate levels – indicating a higher degree of oxidative metabolism [95].
Glioma, a type of brain tumor, comprises glioma stem cells (GSCs) and differentiated tumor cells. While GSCs are linked to malignant glioma progression, differentiated glioma cells can transform into GSCs through a process known as “dedifferentiation.” In hypoxic environments, HIF2α is highly expressed in glioma, regulating dedifferentiation and inducing GSCs [100]. Moreover, elevated HIF2α expression has been observed in gastric cancer specimens [101]. Sphere-derived renal cell carcinoma (RCC) cells also exhibited increased HIF2α expression. The signaling pathways dependent on HIF2α were suggested to contribute to tumor initiation and progression in conventional RCCs [102]. Given that HIF2α is both oncogenic and upregulated in certain cancers, it could potentially serve as another driver of mitochondrial OXPHOS.
Acidosis
Acidosis is a prevalent stressor in the tumor microenvironment (TME), arising from the accumulation and reduced elimination of tumor-derived acids, as well as heightened H+ efflux through membrane-associated H+ transporters and HCO3− exchangers [103]. The extracellular pH in many cancers is observed to be more acidic compared to normal tissues [104, 105]. This acidic environment can disrupt the genetic and transcriptomic profiles of tumor cells, prompting phenotypic adaptations that favor growth and survival in an acidic milieu. The prolonged exposure to acidic pH induces a metabolic shift in tumor cells, maintaining a consistent proliferation rate. Rather than relying on glycolysis, these cells exhibit an increase in reductive glutamine metabolism, driving glutamine-fueled OXPHOS. SIRT1, a deacetylase, plays a role in this metabolic shift by reducing HIF1α activity and increasing HIF2α levels [104]. Furthermore, glucose consumption and lactate production were markedly reduced in several breast cancer cell lines, aligning with the impact of acidosis on glycolysis [105].
Studies employing isotope tracer experiments have revealed that extracellular acidosis augments oxidative pentose phosphate pathway (PPP), glutaminolysis, and fatty acid β-oxidation [106]. The PPP is a crucial metabolic pathway that generates ribose or derivatives and is a significant source of NADPH [105, 106]. Given that NADPH provides protons in reductive biosynthetic reactions, a change in NADPH levels can influence FA and steroid biosynthesis [105].
In an acidic environment, fatty acid oxidation (FAO) and fatty acid synthesis (FAS) can occur simultaneously. Exogenous fatty acid uptake provides the TCA cycle with acetyl-CoA, while glutamine metabolism actively supports citrate production and lipogenesis. These shifts are substantial, as cancer cells adapted to acidic pH predominantly abandon glycolysis in favor of FAO. This not only fuels the TCA cycle with acetyl-CoA but also generates substrates for OXPHOS [107]. For example, the MDA-MB-231 triple-negative and basal-like breast cancer cell line showed a significant increase in both FAs and cholesterol, illustrating their ability to endure metabolic stress [105].
In summary, the chronic adaptation to acidosis in the TME tends to suppress glycolysis while enhancing the metabolism of fatty acids and amino acids, providing increased fuels to drive mitochondrial OXPHOS.
Discussion
Questions pertaining to the temperature
OXPHOS, as the primary ATP provider in eukaryotic cells, has a thermodynamic efficiency of approximately 40 % in animal cells, with the remaining 60 % of energy input being released as heat [1]. Intriguingly, studies have shed light on the local thermogenesis occurring near mitochondria. In one study, a fluorescence polymeric thermometer (FPT) was used to visualize temperature distribution in COS7 cells, revealing local thermogenesis near mitochondria [10]. Another study utilized MitoThermo Yellow (MTY) fluorescence in HEK 293 cells to determine the temperature upon full activation of mitochondrial respiration, which was close to 50 °C [108]. However, challenges exist in accurately calibrating mitochondrial thermogenesis due to technical intricacies related to temperature measurement probes and the response mechanism of the MTY probe [1].
The regulation and functions of UCPs, particularly UCP2, are of interest in cancer research. While downregulation of UCP2 in specific cancer cells may lead to mitochondrial uncoupling and potential temperature rise, the role of UCP2 in cancer is complex. Some cancer cells show enhanced UCP2 expression, and studies indicate a tumor-promoting function associated with UCP2 overexpression [109, 110]. Notably, UCP2 was found to be upregulated in a significant percentage of ovarian and breast tumors [111].
The metabolic behavior of cancer cells in terms of their dependency on OXPHOS and glycolysis varies across different cell lines and stages of cancer progression. Cancer cells can swiftly switch between glycolysis and OXPHOS during carcinogenesis, even with reduced mitochondrial content. The metabolic characteristics of tumors are influenced by their size, growth rate, and genetic features. For example, smaller tumors exhibit low conversion of glucose to lactate but high conversion of glutamate to lactate. Large tumors, on the other hand, demonstrate high utilization rates of both glucose and oxygen. These metabolic variations are vital for understanding tumor bioenergetics and potential therapeutic strategies [112]. Moreover, the characterization of urothelial bladder cancer cell lines revealed distinct metabolic profiles based on genetic features, shedding light on the complex bioenergetic remodeling in cancer [113].
Acidosis has profound effects on cancer cell metabolism. It leads to a decrease in the consumption of both oxygen and glucose and a reduction in glycolysis [105]. Monocarboxylate transporter 4 (MCT4), a lactate/H+ symporter, plays a crucial role in facilitating H+ efflux from hypoxic cancer cells and releasing lactate, which is the end-product of glycolysis. Interestingly, lactate can also be captured by MCT1 and converted back to pyruvate, highlighting its dynamic role in cellular metabolism [114]. Contrary to expectations, exposure to lactic acidosis in breast cancer cell lines promotes glycolysis, leading to an elevated extracellular acidification rate (ECAR) [105]. However, tumors experiencing lactic acidosis have been linked to positive clinical outcomes, potentially due to the redirection of energy utilization from anaerobic respiration by inhibiting glycolysis. Lactic acidosis seems to repress the glycolytic phenotype by simultaneously reducing glucose consumption and lactate production in tumor cells, presenting a complex interplay between acidosis and cancer cell metabolism. Understanding these intricate metabolic adaptations is crucial for developing targeted therapeutic approaches in cancer treatment [115].
Therapeutic strategies
Mitochondria play pivotal roles in cancer progression, making them an attractive target for cancer therapies, particularly those focusing on metabolic pathways [116], [117], [118], [119], [120]. ATP/Ca2+ pump purinergic receptor 4 (P2XR4), located on endolysosomes, is a key player in tumor metabolism through Ca2+ homeostasis. Higher expression of P2XR4 has been linked to increased cancer cell migration, survival, tumor progression, and vesicular trafficking. Inhibition of P2XR4, either through pharmacological means or genetic disruption, led to reduced mitochondrial and glutathione activity, antioxidant response, and increased cell death in clear cell renal cell carcinoma models [121].
Another target for cancer therapy is BTB and CNC homology 1 (BACH1), a haem-binding transcription factor upregulated in triple-negative breast cancer (TNBC) cells. BACH1 negatively regulates the transcription of genes involved in the ETC and decreases glucose utilization in the TCA cycle. Inhibiting BACH1 resulted in enhanced mitochondrial respiration, increased levels of TCA cycle metabolites, and elevated ATP levels in TNBC cells. Inhibitors of ETC complexes were effective in reducing cell growth and viability in BACH1-depleted cells [122]. Additionally, using atovaquone (AVO), an inhibitor of ETC complex III, in combination with hemin, showed promising results in inhibiting tumor growth in TNBC treatment. An innovative approach using an ATP-responsive nanoplatform delivered these drugs to tumor mitochondria, inducing apoptosis and inhibiting tumor growth [123]. These targeted therapies underscore the potential of mitochondrial-focused interventions in cancer treatment.
The potential heat generated from mitochondrial OXPHOS in cancer cells presents an intriguing opportunity to address drug resistance. Researchers have explored a poly(N-isopropylacrylamide) (PNIPAM)-based thermoresponsive nanocarrier with mitochondria-targeting modifications loaded with drugs such as doxorubicin and paclitaxel. These nanocarriers were designed to exploit the higher temperature of cancer cell mitochondria compared to normal cells. In the case of doxorubicin, the nanocarrier system successfully delivered the drug to the mitochondria of small-cell lung cancer cells [124]. Similarly, paclitaxel-encapsulated PNIPAM-based nanoparticles exhibited effective drug delivery and rapid release within the mitochondria of murine bladder cancer cells [125].
In summary, the exploration of mitochondrial thermogenesis in cancer cells, both theoretically and experimentally, sheds light on its potential role. While the elevation of mitochondrial temperature has been observed in certain cancer cells at specific stages, further research is crucial to establish consistent patterns and insights. These insights could pave the way for the development of innovative treatments aimed at leveraging mitochondrial thermogenesis to combat drug resistance in cancer.
Funding source: National High Level Hospital Clinical Research Funding
Award Identifier / Grant number: 2022-PUMCH-E-004
Funding source: Beijing Municipal Natural Science Foundation
Award Identifier / Grant number: 7212212
Acknowledgments
The authors would like to express their gratitude to Beijing Municipal Natural Science Foundation for the financial support.
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Research ethics: Not applicable.
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Informed consent: Not applicable.
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Author contributions: The authors confirm their contribution to the paper as follows: study conception and design: XYZ, YH; data collection: XYZ; analysis and interpretation of results: XYZ, YH; draft manuscript preparation: XYZ. All authors reviewed and approved the final version of the manuscript.
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Competing interests: Authors state no conflict of interest.
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Research funding: Beijing Municipal Natural Science Foundation (7212212), National High Level Hospital Clinical Research Funding (2022-PUMCH-E-004).
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Data availability: Not applicable.
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Articles in the same Issue
- Frontmatter
- Review Articles
- Mitochondrial thermogenesis in cancer cells
- Application of indocyanine green in the management of oral cancer: a literature review
- Long non-coding RNA, FOXP4-AS1, acts as a novel biomarker of cancers
- The role of synthetic peptides derived from bovine lactoferricin against breast cancer cell lines: a mini-review
- Single cell RNA sequencing – a valuable tool for cancer immunotherapy: a mini review
- Research Articles
- Global patterns and temporal trends in ovarian cancer morbidity, mortality, and burden from 1990 to 2019
- The association between NRF2 transcriptional gene dysregulation and IDH mutation in Grade 4 astrocytoma
- More than just a KRAS inhibitor: DCAI abrogates the self-renewal of pancreatic cancer stem cells in vitro
- DUSP1 promotes pancreatic cancer cell proliferation and invasion by upregulating nephronectin expression
- IMMT promotes hepatocellular carcinoma formation via PI3K/AKT/mTOR pathway
- MiR-100-5p transfected MSCs-derived exosomes can suppress NSCLC progression via PI3K-AKT-mTOR
- Inhibitory function of CDK12i combined with WEE1i on castration-resistant prostate cancer cells in vitro and in vivo
- Prognostic potential of m7G-associated lncRNA signature in predicting bladder cancer response to immunotherapy and chemotherapy
- Case Reports
- A rare FBXO25–SEPT14 fusion in a patient with chronic myeloid leukemia treatment to tyrosine kinase inhibitors: a case report
- Stage I duodenal adenocarcinoma cured by a short treatment cycle of pembrolizumab: a case report
- Rapid Communication
- ROMO1 – a potential immunohistochemical prognostic marker for cancer development
- Article Commentary
- A commentary: Role of MTA1: a novel modulator reprogramming mitochondrial glucose metabolism
Articles in the same Issue
- Frontmatter
- Review Articles
- Mitochondrial thermogenesis in cancer cells
- Application of indocyanine green in the management of oral cancer: a literature review
- Long non-coding RNA, FOXP4-AS1, acts as a novel biomarker of cancers
- The role of synthetic peptides derived from bovine lactoferricin against breast cancer cell lines: a mini-review
- Single cell RNA sequencing – a valuable tool for cancer immunotherapy: a mini review
- Research Articles
- Global patterns and temporal trends in ovarian cancer morbidity, mortality, and burden from 1990 to 2019
- The association between NRF2 transcriptional gene dysregulation and IDH mutation in Grade 4 astrocytoma
- More than just a KRAS inhibitor: DCAI abrogates the self-renewal of pancreatic cancer stem cells in vitro
- DUSP1 promotes pancreatic cancer cell proliferation and invasion by upregulating nephronectin expression
- IMMT promotes hepatocellular carcinoma formation via PI3K/AKT/mTOR pathway
- MiR-100-5p transfected MSCs-derived exosomes can suppress NSCLC progression via PI3K-AKT-mTOR
- Inhibitory function of CDK12i combined with WEE1i on castration-resistant prostate cancer cells in vitro and in vivo
- Prognostic potential of m7G-associated lncRNA signature in predicting bladder cancer response to immunotherapy and chemotherapy
- Case Reports
- A rare FBXO25–SEPT14 fusion in a patient with chronic myeloid leukemia treatment to tyrosine kinase inhibitors: a case report
- Stage I duodenal adenocarcinoma cured by a short treatment cycle of pembrolizumab: a case report
- Rapid Communication
- ROMO1 – a potential immunohistochemical prognostic marker for cancer development
- Article Commentary
- A commentary: Role of MTA1: a novel modulator reprogramming mitochondrial glucose metabolism
