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Implications of the mitochondrial CB1 receptor in the brain: from mitochondrial dysfunction to neuroprotection

  • Ari Misael Martínez-Torres , Keyla Tamara Cerdán-Centeno , Crisalde Ramirez-Celis , Suly Peniche-Zamudio , Teresa de Jesús Durán-González , Camila Roa-Gutierrez , Cynthia Navarro-Mabarak and Julio Morán EMAIL logo
Published/Copyright: October 22, 2025
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Reviews in the Neurosciences
From the journal Reviews in the Neurosciences

Abstract

Mitochondrial activity is essential for brain function, as ATP produced by mitochondria is crucial for neuronal activity, growth, and regeneration. Bioenergetic failure is a hallmark in neurodegenerative and acquired brain diseases and converts the mitochondria into a molecular target to prevent neuronal death. Mitochondrial regulation can play a crucial role in energetic balance, calcium homeostasis, and neuronal signaling. Different molecules have been implicated in the regulation of this organelle, and recently, the endocannabinoid system (ECS) became a relevant mitochondrial regulator through the mitochondrial CB1 receptor (mtCB1R). The recent discovery of this receptor and its participation in mitochondrial homeostasis opens new insights about its role in neuronal plasticity and neurodegeneration. This review briefly describes the endocannabinoid system, with a major focus on mtCB1R and its role in mitochondrial homeostasis, learning, memory, and neuronal death. Relevant aspects of the role of mtCB1R in the brain in health and diseases remain unclear; however, exploring this topic holds promising implications in the comprehension of mitochondrial degeneration and future therapeutic advantages.

Keywords: cannabinoids; mtCB1; endocannabinoid system; mitochondrial dysfunction; neurodegeneration

1 Introduction

Neuronal death is implicated in neurodegenerative and acquired brain diseases, which represent a common cause of mortality or morbidity worldwide. Therapeutic strategies are aimed at delaying or limiting neuronal dysfunction, avoiding death or the development of sequelae in patients. However, the identification of molecules involved in neuronal death continues to be an active area of research. The molecular mechanisms implicated in neuronal death result from a combination of environmental and genetic factors, including protein misfolding, oxidative stress, excitotoxicity, inflammation, and mitochondrial dysfunction (Angelova and Abramov 2024), which will be the focus of this review.

Mitochondria are tubular or globular organelles surrounded by a double membrane: the outer membrane separates the organelle from the cytosol, while the inner membrane forms the matrix and the cristae. Neurons contain thousands of mitochondria, which are essential for maintaining their structural integrity and functional activity.

The brain activity leads to high production and consumption of adenosine triphosphate (ATP). In the human brain, the rate of ATP consumption is higher in grey matter in comparison with white matter, and cortical neurons are the highest consumers (Zhu et al. 2012). In mitochondria, ATP production through oxidative phosphorylation demands a high oxygen supply, about 20 % of the body’s total oxygen consumption is used for this process (Siwicka-Gieroba et al. 2022). In addition, other metabolic aspects are regulated by this organelle, including calcium dynamics. Mitochondria modulate intracellular Ca2+ signaling in neurons by regulating cytosolic Ca2+ concentrations (Bravo-Sagua et al. 2017). In turn, cytosolic Ca2+ regulates the production of reactive oxygen species (ROS) through the activation of ROS producing enzymes (Angelova and Abramov 2024). Alterations of ATP production and Ca2+ dynamics can lead to neuronal dysfunction, a feature of both acquired and neurodegenerative brain disorders.

2 Mitochondrial dysfunction in neurodegenerative and acquired brain diseases

Mitochondrial dysfunction is a pathological condition leading to cellular energy depletion and eventual cell death (Bustamante-Barrientos et al. 2023). This dysfunction is characterized by several molecular and cellular defects that contribute to the progression of neuropathological disorders (Klemmensen et al. 2024). As key source of ATP production via the mitochondrial respiratory chain, mitochondria are essential for neuronal function and various cellular signaling pathways; impairments in these processes can result in neurodegeneration (Wang et al. 2019) (Figure 1).

Figure 1: Mitochondrial dysfunction leads to molecular events associated with alterations in neuronal activity and death. Cerdán-Centeno (2025a) https://BioRender.com/lutov8c.
Figure 1:

Mitochondrial dysfunction leads to molecular events associated with alterations in neuronal activity and death. Cerdán-Centeno (2025a) https://BioRender.com/lutov8c.

Additionally, mitochondria are a major source of ROS, which are vital for maintaining redox homeostasis. Under normal physiological conditions, approximately 1–3% of the molecular oxygen that enters the mitochondrial electron transport chain is reduced but lead to the formation of superoxide anion (O2−) as a byproduct (Wong et al. 2017). Endogenous antioxidant systems such as superoxide dismutases (Mn-SOD in the mitochondrial matrix and Cu/Zn-SOD in the cytosol) facilitate the detoxification of mitochondrial superoxide, transforming it into H2O2. However, pathological conditions can impair the function of these antioxidant enzymes, leading to an accumulation of ROS that can oxidize various biomolecules. This oxidative damage may result in structural alterations, aggregation of cellular components and functional loss. Increased production of ROS contributes to oxidative stress, a significant factor associated with the aging process and linked to the onset of neurodegenerative diseases (Lin and Beal 2006).

In neurons, as previously mentioned, mitochondria also regulate intracellular calcium levels, and their dysfunction can activate cell death pathways (Chen et al. 2023). Mitochondria are also crucial in the control of membrane excitability, synaptic plasticity, and neurotransmission, which renders them incredibly susceptible to mitochondrial dysfunction (Devine and Kittler 2018). Given the fully differentiated and non-renewable nature of neurons, maintaining mitochondrial integrity is critical for their survival and relies on mechanisms that counteract dysfunction (Misgeld and Schwarz 2017). Sustained mitochondrial damage disrupts mitochondrial complexes, leading to energy deficits, excessive ROS production, and reduced calcium buffering capacity.

Additionally, genetic mutations in mitochondrial and nuclear DNA impair mitochondrial biogenesis, dynamics, and stress response, exacerbating neurodegeneration (Song et al. 2024). Structural changes, such as mitochondrial fragmentation and impaired fusion, may disrupt mitochondrial networks and compromise cellular health (Jenkins et al. 2024). Neurodegeneration is associated with significant alterations in several mitochondrial processes, including mitochondrial clearance, biogenesis, and dynamics, such as fusion and fission events, which affect mitochondrial quality (Antico et al. 2025).

During metabolic stress, several pathological events occur, including the loss of mitochondrial membrane potential, the opening of the mitochondrial permeability transition pore (mPTP), the release of cytochrome c into the cytosol, leading to the activation of the intrinsic apoptotic pathway, and mitophagy (Chen et al. 2023). These disruptions contribute to the overall decline in mitochondrial function, exacerbating neurodegenerative processes.

In several neuropathological conditions, such as ischemia-reperfusion (I/R) injury, a hallmark of ischemic stroke, mitochondrial dysfunction has been considered as a key contributor to disease progression. I/R injury occurs when blood supply is restored following a period of ischemia, paradoxically leading to additional tissue damage. During acute ischemia, oxygen, and glucose deprivation rapidly impair neuronal sodium (Na+) ion channels, causing cell swelling, degeneration, and necrosis (Iadecola and Anrather 2011).

During hypoxic conditions, several proteins are induced, including the hypoxia-inducible factor-1 (HIF-1) that modulates over 700 genes with both protective and detrimental effects (Wu et al. 2019). HIF-1 interacts with the von Hippel–Lindau (VHL) gene to inhibit protease activity, while activating pro-inflammatory and apoptotic pathways via nuclear factor κB (NF-κB), exacerbating hypoxia by increasing metabolic demand (Vatte and Ugale 2023). Hypoxia also induces HIF-1-dependent mitophagy, reducing metabolic substrates and accumulating waste, which disrupts calcium homeostasis, impairs oxidative phosphorylation (OXPHOS), and diminishes ATP production. These processes trigger the opening of the mPTP, further aggravating cellular damage (Lesnefsky et al. 2017).

Mitochondria are the primary source of ROS during early reperfusion, highlighting their central role in the mechanisms that drive tissue injury in I/R events. Upon reperfusion, the restoration of blood flow leads to an increase in ROS, which are key mediators of metabolic disturbance and inflammation. ROS contribute to cellular damage through mechanisms such as lipid peroxidation, DNA oxidation, and the activation of matrix metalloproteinases and calpains (Eltzschig and Eckle 2011). ROS can also interact with nitric oxide (NO), fatty acids, or free iron, leading to the generation of highly reactive species like peroxynitrite and hydroxyl radicals, which further exacerbate cell death (Juan et al. 2021).The dynamics of mitochondrial function are crucial in understanding the etiology of reperfusion injuries (Hernansanz-Agustín and Enríquez 2021). Thus, mitochondrial dysfunction during I/R involves a complex interplay of metabolic disturbances, inflammatory responses, and oxidative stress.

Traumatic brain injury (TBI), a form of acquired brain injury, is significantly influenced by mitochondrial dysfunction, with persistent neurometabolic changes underlying its chronic pathological features (Carteri 2025). The pathogenesis of TBI involves a biphasic process: a primary mechanical injury and a secondary delayed injury (Karin and Alon 2017). The primary injury occurs immediately following the trauma, which results from the acute mechanical disruption of brain tissue and cellular architecture. This mechanical injury leads to damage of axons and synapses, which can cause excitotoxic injury (Prins et al. 2013). The initial mechanical damage can trigger secondary effects, leading to progressive neurodegeneration.

The secondary injury usually develops hours to weeks after the initial trauma it is characterized by maladaptive processes such as mitochondria-specific lipid oxidation, inflammation, and the initiation of regulated cell death pathways. These mechanisms closely resemble those observed in other acute brain injury conditions, including I/R injury, spinal cord injury, and subarachnoid hemorrhage (de Macedo Filho et al. 2024). Clinical and experimental studies have demonstrated that mitochondrial injury plays a critical role in the pathogenesis of TBI. Mitochondrial dysfunction is a critical factor in the complex biochemical cascades following TBI, leading to oxidative stress and impaired cellular energy production; it is also the primary contributor to neuronal loss and poor clinical outcomes following TBI (Cheng et al. 2012).

Mitochondrial dysfunction and the overproduction of ROS are critical consequences of TBI, significantly contributing to the onset of neuroinflammation (Palma et al. 2024). Key features of mitochondrial dysfunction include reduced oxidative phosphorylation capacity, mitochondrial swelling, and electron transport system disruption, all of them elevate ROS levels and diminish energy production. These mitochondrial alterations trigger cascades of events that can result in neuronal death persisting for days post-injury (Hubbard et al. 2024). The interplay between mitochondrial dysfunction and ROS generation underscores their role in the TBI-associated neuroinflammatory responses, ultimately driving the neurological deficits observed in affected individuals.

3 The endocannabinoid system

The ECS is a complex neuromodulatory system with wide expression throughout the brain. This biological network comprises the cannabinoid receptors (Basavarajappa et al. 2009), their ligands arachidonoyl ethanol amide (anandamide or AEA) and 2-arachidonoyl glycerol (2-AG) (Gobira et al. 2019), as well as the enzymes responsible for their synthesis and degradation. Each of the components plays a critical role in maintaining homeostasis and regulating several physiological processes.

The ECS is a highly conserved and evolutionary ancient biological system. Analysis carried out by BLAST (Basic Local Alignment Search tool) of the GenBank database suggests that endocannabinoid molecules have occurred as far back as the unicellular eukaryotic common ancestor of plants and animals, given that the machinery for the biosynthesis and degradation of anandamide and 2-AG has been characterized in Arabidopsis and Nicotiana tabacum (Elphick and Egertová 2005). These molecules have participated in different signaling cascades across independent lineages during the evolution of eukaryotes (Elphick and Egertová 2005).

Moreover, phylogenetic analysis suggests that ortholog genes of the CB1 receptor occur in 65 mammalian species, four non-mammalian vertebrates, and one invertebrate (urochordates; the deuterostomian invertebrate Ciona intestinalis), but not protostomian invertebrates (Drosophila, Caenorhabditis elegans), showing a relatively scarce distribution in the animal kingdom (McPartland et al. 2006). The canonical cannabinoid receptors share around 44 % sequence similarity, indicating that they arose from duplication of a common ancestral gene. In addition, their low sequence similarity with other GPCRs in mammals further denotes an evolutionarily ancient whole-genome duplication event in a common ancestor of extant vertebrates, more specifically in the deuterostomian branch of the animal kingdom, after the deuterostomian-protostomian split (Elphick 2012). Furthermore, the presence of cannabinoid binding sites in the Mytilus and Hirudo species, but not in insects, points to the loss of the gene in the ecdysozoan lineage (Elphick and Egertová 2005).

3.1 Cannabinoid receptors

The most widely distributed cannabinoids receptors are the Type 1 and Type 2 cannabinoid receptors (CB1R and CB2R). It has been proposed that other receptors can also interact with endocannabinoids, such as the transient receptor potential vanilloid type 1 (TRPV1), the transient receptor potential of melastatin type 8 (TRPM8), the peroxisome proliferator-activated receptor (PPAR) and the novel receptors GPR55 and GPR119.

CB1R and CB2R are G protein-coupled receptors (GPCRs), composed of seven transmembrane segments, an extracellular amino terminus, and an intracellular carboxyl terminus, associated with a pertussis toxin (PTX)-sensitive G protein (Howlett 2004; Mukhopadhyay et al. 2000). In neurons, these receptors are generally coupled to Gi/o protein, whereas astrocytes present receptors couple to Gq protein, which directly affects the downstream effectors (Eraso-Pichot et al. 2023). The activated G-protein then interacts with adenylyl cyclase and mitogen-activated protein kinase, triggering downstream molecular pathways that ultimately activate a specific cellular response. Although the CB1R and CB2R share 48 % similarity in amino acid sequence, they differ in structure, function, and the molecular pathways activated in different tissues (Mechoulam and Parker 2013).

3.2 CB1R

The CB1R is one of the most abundant GPCRs in the central nervous system (Basavarajappa et al. 2017). It is highly expressed by neurons in regions related to motor control, cognition, and memory processing, including the basal ganglia, the molecular layer of the cerebellum, and specific areas of the hippocampus (Kendall and Yudowski 2017). Additionally, CB1R are expressed, to a smaller extent, in the hypothalamus, brainstem, and spinal cord (Nguyen et al. 2012). These receptors are particularly enriched in both pre- and post-synaptic terminals, suggesting a critical role in modulating neurotransmission.

The CB1R has also been identified in mitochondria, particularly in the outer in the membrane within the hippocampus suggesting a potential role in the regulation of neuronal energy metabolism (Bénard et al. 2012).

Other cell types, such as astrocytes, oligodendrocytes, oligodendrocyte precursors, and microglia, also show a subtle expression of CB1R (Lu and Mackie 2021). In the periphery, the CB1R is present in gastrointestinal tract, liver, pancreas, muscle, and adipose tissue (Mendizabal-Zubiaga et al. 2016; O’Sullivan et al. 2021). During embryonic development, the receptor is found in white matter and subventricular areas, showing a dynamic expression during neural development (Rodrigues et al. 2024).

3.3 CB2R

CB2R levels in the brain are lower compared to CB1R (Basavarajappa et al. 2009). Initially, these receptors were proposed to be exclusive to peripheral immune cells (Munro et al. 1993). Subsequent studies, however, demonstrated that apart from cells of the macrophage lineage (Carlisle et al. 2002), the CB2R can also be found in brain microglia (Bockmann et al. 2023). Interestingly, pathological contexts like inflammation upregulate the CB2R expression levels in microglia, demonstrating an adaptative response of the receptor in different conditions (Ashton and Glass 2007; Atwood and Mackie 2010).

Additionally, the CB2R has also been detected in neurons, where it can modulate synaptic function (Kendall and Yudowski 2017). In the gastrointestinal tract, this receptor is found in enteric neurons and epithelial cells (Sharkey and Wiley 2016). In addition, CB2R is present in neural progenitors during embryonic stages up to adulthood and in microglial cells and macrophages during development (Ruiz-Contreras et al. 2022).

3.4 CB1R and CB2R signaling pathways

The signaling pathways activated by CB1R and CB2R can vary depending on cell type, and ligand. For example, THC is a low-potency agonist compared to 2-AG and synthetic cannabinoids, which may lead to different effects at molecular and behavioral levels (Lu and Mackie 2021). The modulation of adenylyl cyclase (AC) activity is the common intracellular effect observed by CB1R and CB2R activation, leading to low production of cAMP (Kendall and Yudowski 2017). In the presynaptic terminal, the inhibition of voltage-gated calcium channels through the activation of CB1R and CB2R can reduce the intracellular calcium levels, modulating neuronal excitability and the release of neurotransmitter, such as GABA, glutamate, serotonin, acetylcholine, and dopamine (Basavarajappa et al. 2017). In addition, the stimulation of potassium inwardly rectifying potassium (GIRK) channels hyperpolarizes neurons, reducing their excitability and the likelihood of firing action potentials (Kendall and Yudowski 2017).

The association of the CB1R with scaffolding proteins such as β-arrestins mediates the receptor internalization upon continuous stimuli, as well as the activation of signaling cascades such as MAPK, ERK1/2, JNK1/2/3, CREB and P38α (Kendall and Yudowski 2017). These pathways participate in the regulation of cellular processes such as proliferation, cell cycle progression, cell death/survival, synaptic plasticity, and neuronal growth (Bockmann et al. 2023). CB1R activation can also promote activation of the PI3K/AKT pathway, related to the modulation of cell growth and survival (Mukhopadhyay et al. 2010). CB1R activation has been shown to promote the PI3K/Akt/mTORC1 pathway, leading to increased expression of brain-derived neurotrophic factor (BDNF), thereby suggesting a potential neuroprotective mechanism (Blázquez et al. 2015).

3.5 Endocannabinoids, synthesis, and degradation

The two main endocannabinoids found in animals result from the remodeling of membrane phospholipids (Di Marzo 2011). The first identified endocannabinoid N-arachidonoyl-ethanolamine (AEA), also called anandamide, was found in porcine brain extracts (Devane et al. 1992). Three years later, 2-arachidonoyl-glycerol (2-AG) was characterized as a ligand for both CB1R and CB2R (Mechoulam et al. 1995; Sugiura et al. 1995). Other molecules have also been proposed as potential endocannabinoids. Among them, N-oleoyl-dopamine (OLDA), an endogenous long-chain fatty acid amide, has been shown to activate TRPV1, leading to hyperalgesia (Chu et al. 2003).

In addition, monoacylglycerols have been shown to interact with components of the endocannabinoid system. For example, both 2-arachidonoylglycerol ether (noladin ether) and N-arachidonoyl-dopamine (AA-DA) interact with CB1R and CB2R. Notably, AA-DA exhibits greater selectivity for CB1R than anandamide, and in mice, it induces the characteristic cannabinoid tetrad of effects: hypothermia, hypo-locomotion, catalepsy, and analgesia (Bisogno et al. 2000). Additionally, other structurally related compounds also produce endocannabinoid-like signaling. For example, two-oleoyl-glycerol (2-OG) produces anorexigenic effects by activating GPR119 (Iannotti et al. 2016).

Unlike neurotransmitters that are stored in vesicles, endocannabinoids have an “on-demand” production, interacting with phospholipid domains and lipid acceptors like serum albumin (Nicolussi and Gertsch 2015). In the case of 2-AG, its production is triggered by the elevation of intracellular Ca2+ after the activation of voltage-gated calcium channels (VGCCs) (Castillo et al. 2012). It has also been identified that glutamatergic neurotransmission may also activate the production of 2-AG in the post-synaptic neuron. Specifically, mGluR1 and mGluR5, along with the muscarinic acetylcholine receptor M1, activate the Gq/11 subunit, significantly stimulating the β isoform of phospholipase C (PLC-β). This activation converts 2-arachidonate-containing phosphoinositides into 2-arachidonoyl-containing diacylglycerols (DAGs) (Iannotti et al. 2016). Diacylglycerol lipase (DAGL) then hydrolyzes DAG, releasing 2-AG (Okazaki et al. 1981). DAGLβ−/− mice show a 50 % reduction in brain 2-AG levels, while DAGL−/− mice exhibit an 80 % decrease in 2-AG. These findings suggest that DAGL plays a more critical role in 2-AG synthesis than DAGLβ (Gao et al. 2010). An alternative pathway for 2-AG formation involves its rapid conversion from 2-arachidonoyl-lysophosphatidic acid by lysophosphatidic acid phosphatase (Nakane et al. 2002).

The classical pathway for AEA biosynthesis begins with the N-acylation of ethanolamine phospholipids by Ca2+-dependent N-acyltransferase (Ca-NAT), induced by an increase in intracellular Ca2+ levels (Di Marzo 2011). Then, the N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) hydrolyzes these molecules into AEA (Ueda et al. 2013). This endocannabinoid may be synthesized through the double acetylation of NArPE by α, β-hydrolase domain 4 (ABHD4), producing glycerophospho-N-acylethanolamine (GP-NAE) (Mock et al. 2023), which is hydrolyzed by glycerophosphodiester phosphodiesterase 1 (GDE1), yielding AEA. However, the role of this pathway in selectively synthetizing AEA is uncertain, as there are no specific enzymatic precursors (Ueda et al. 2013). Additionally, neuronal phospholipase C (PLC) has been shown to hydrolyze NArPE into NAE phosphate, which is dephosphorylated to AEA by protein tyrosine phosphatase PTPN22 (Iannotti et al. 2016).

Regarding degradation, the primary enzyme exhibiting the highest catalytic activity is the serine hydrolase monoacylglycerol lipase (MAGL), which is responsible for hydrolysis of approximately 85 % of 2-AG, while the remaining hydrolysis is carried out by the enzymes ABHD6, ABHD12, and fatty acid amide hydrolase (FAAH) (Blankman et al. 2007). This enzymatic reaction results in the conversion of 2-AG into arachidonic acid (AA) and glycerol.

The hydrolysis of AEA is primarily performed by the fatty acid amide hydrolase-1 (FAAH-1), which converts anandamide into ethanolamine and free fatty acids (Ueda et al. 2013). In contrast, a different variant of the fatty acid amide hydrolase, designated as FAAH-2, is expressed in humans, but not in mice, and preferentially hydrolyzes the sleep-inducing compound N-oleoyl-ethanolamine (oleamide) (Wei et al. 2006). Both endocannabinoids, AEA and 2-AG, can also be degraded via cyclooxygenase-2 (COX-2) by converting AEA and 2-AG into prostaglandin E2 ethanolamide and AA, respectively (Simard et al. 2022; Yu et al. 1997). The induction of this enzyme can be triggered by cytokines and inflammatory mediators present in oligodendrocytes and microglia. Alternatively, AEA and 2-AG can be oxygenated by lipoxygenases (LOXs), primarily known for their role in synthesizing various immunomodulatory lipid signaling molecules (Mock et al. 2023). Specifically, 15-LO-1 leads the conversion of anandamide into its 15-hydroxy derivative, 15-HETE-EA, while the 15-LO-2 isoform converts 2-AG into 15-HETE-G in humans (Simard et al. 2022).

4 Physiological roles of the ECS in the brain

AEA is a member of a family of N-acylethanolamines (NAE) found in the brain and peripheral tissues. The most abundant NAE of the mammalian brain are the endocannabinoid-like N-palmitoylethanolamine (PEA), followed by N-stearoylethamolamine (SEA) and N-oleoylethanolamine (OEA). AEA represents only <10 % of total. The actions of these endocannabinoid-like mediators are not mainly mediated by CB1R or CB2R. For example, PEA primarily targets the nuclear receptor PPARα and the receptors GPR55 and GPR119 (Redlich et al. 2014; Rankin and Fowler 2020). Interestingly, PEA inhibits AEA degradation, modulating the activation of the CB1R and CB2R (Beggiato et al. 2019; Rankin and Fowler 2020). OEA, PEA, and virodhamine modulate blood-brain barrier permeability by activating PPARα receptors in models of cerebral ischemia induced by middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation, respectively (Hind et al. 2015; Zhou et al. 2012).

It has been proposed that AEA modulate several biological and behavior processes, including body temperature control, locomotion (Huitrón-Reséndiz et al. 2001), appetite (Williams and Kirkham 1999), pain perception (Guindon and Hohmann 2009), anxiety and fear (Kathuria et al. 2003; Marsicano et al. 2002). As mentioned, AEA can bind not only CB1R and CB2R, but also to TRPV1, TRPM8, PPARα and PPARγ which explains, its involvement in diverse physiological processes. However, most of the biological effects of AEA results from its high affinity binding to CB1R.

Cannabinoid receptors are expressed in regions such as the amygdala, prefrontal cortex, hippocampus, and globus pallidus (Glass et al. 1997), which suggests a role in the reward circuit, particularly through interactions with dopaminergic networks in the ventral tegmental area and the nucleus accumbens (Parsons and Hurd 2015). These networks are critical for processing motivation, pleasure, and reinforcement-related behaviors.

Additionally, cannabinoid signaling may influence emotional regulation, particularly through the activation of 5-HT1A receptors, as observed using compounds such as cannabidiol. This interaction has been shown to modulate amygdala activity, contributing to anxiolytic effects and emotional stability (Blessing et al. 2015; Russo et al. 2005). These studies highlight the interplay between the endocannabinoid and other neurotransmitter systems.

One of the most well-documented mechanisms of cannabinoids is their ability to modulate neurotransmitter release, directly influencing the excitatory-inhibitory balance of neural circuits. This action is primarily mediated through CB1R activation, which regulates the presynaptic release of several neurotransmitters. CB1R activation triggers the release of the Gβγ heterodimer, which then interacts with N-type Ca2+ channels and the A-type inward rectifying K+ channels, leading to the inhibition of neurotransmitter release (Howlett 2004). This process plays a crucial role in regulating excessive excitatory signaling mediated by glutamate (Gerdeman and Lovinger 2001; Wilson and Nicoll 2002; Zou and Kumar 2018).

Beyond presynaptic neurotransmitter modulation, cannabinoids can regulate glutamatergic neurotransmission through receptor internalization mechanisms. Particularly, CBR1 activation induces the internalization of the NR1 subunit of NMDA receptors mediated by the association of the scaffolding protein HINT1 with the CB1R and the NR1 subunit. This association reduces the availability and responsiveness of the receptor (Sánchez-Blázquez et al. 2013; Vicente-Sánchez et al. 2013).

5 Effects of cannabinoids on mitochondrial function

Several studies have evidenced a link between cannabinoid signaling and mitochondrial function. Initially, cannabinoids were hypothesized to act directly and non-specifically on mitochondria due to their high lipophilicity, affecting NADH oxidase activity and ATP synthesis (Bartova and Birmingham 1976; Chari-Bitron and Bino 1971). Subsequent in vitro studies demonstrated that THC could uncouple state IV respiration, leading to mitochondrial swelling and the release of matrix enzymes. These effects were attributed to the destabilization of the phospholipid cardiolipin (Bartova and Birmingham 1976; Chari-Bitron and Bino 1971). However, evidence suggested a specific action, as THC dose-dependently altered mitochondrial shape, correlating with changes in oxygen uptake (Bino et al. 1972). Finally, in 1988, Devane and colleagues demonstrated the existence of cannabinoid receptors in the brain (Devane et al. 1988), which opened a new field for the study of numerous processes mediated by the ECS.

Cannabinoids have been identified as modulators of mitochondrial processes, such as energy balance and metabolism (Bénard et al. 2012). Further studies on the effect of THC and CBD demonstrated that THC disrupted mitochondrial function and inhibited respiration, ultimately leading to cell death (Sarafian et al. 2003). Morphological dose-dependent changes in mitochondria were also observed in vivo following THC administration to rats, suggesting the presence of structures sensitive to this compound (Banerji et al. 1985).

Cannabinoids control numerous processes in the mitochondria, such as the regulation of the mitochondrial electron transport chain (ETC) (Athanasiou et al. 2007; Singh et al. 2015), mitochondrial membrane potential (Elmazoglu et al. 2020; Movsesyan et al. 2004), energy production (Cosentino et al. 2024; Fišar et al. 2014), ROS formation (Athanasiou et al. 2007; Maya-López et al. 2024), fission and fusion dynamics (da Silva et al. 2014; Walker et al. 2020), mitophagy (Kataoka et al. 2020; B. Liu et al. 2022), and mitochondrial biogenesis (Bai et al. 2017), among others.

There is contrasting evidence regarding the effects of cannabinoids on electron transport chain (ETC) complex activity, which differs depending on the type of cannabinoid and the cell type analyzed. For example, Singh et al. (2015) found that among all tested cannabinoid receptor agonists, only anandamide significantly increased complex I activity, while anandamide, THC, WIN55,212–2, AM251 and cannabidiol, strongly inhibited complex II/III and IV function. Additionally, THC was the only cannabinoid found to decrease citrate synthase activity. Authors suggest that these actions are not mediated by a specific receptor (Singh et al. 2015).

It is important to note that although cannabidiol suppresses the function of all the ETC complexes, it exerts a neuroprotective effect in primary hippocampal cultures against mitochondrially acting toxins and H2O2. In this regard, co-treatment of cells with cannabidiol and oligomycin, an ATP synthase inhibitor, shows a protective mechanism of cannabinoids, probably acting at the mitochondrial level. Indeed, the mitochondrial depolarization by the ATP uncoupler FCCP was prevented by cannabidiol at concentrations of 100 nm and 1 µm (Ryan et al. 2009).

Cannabinoids also influence mitochondrial hydrogen peroxide production in a concentration-dependent manner in the rat heart cell line H460 (Athanasiou et al. 2007). In this study, anandamide did not modify the mitochondrial levels of H2O2, whereas both THC and HU-210 caused a concentration-dependent increase in ROS production. In addition, all three cannabinoids cumulatively decreased mitochondrial membrane potential. The rise in mitochondrial H2O2 formation in response to THC might result from the general mitochondrial dysfunction exerted by this cannabinoid (Athanasiou et al. 2007).

The activation of the CB1R regulates mitochondrial dynamics, including fusion and fission, processes that allow mitochondria to modify their shape, number, size, and distribution (Senese et al. 2024). Briefly, fission creates new mitochondria and participates in the quality control of this organelle through the clearance of impaired mitochondria, while fusion mitigates stress by mixing and exchanging the contents of compromised mitochondria as a complementation strategy (Youle and van der Bliek 2012). A balanced transition between both processes is crucial to ensure mitochondrial function, adapting the network formed by this organelle to respond to different metabolic states and the nutrients on the microenvironment (Wai and Langer 2016). In fact, alterations in fusion and fission events may result in a fragmented or hyperfused network of mitochondria, leading to the dysfunction of this organelle observed in various acquired and degenerative diseases (Tilokani et al. 2018).

It was shown that, in placental BeWo cells, THC disturbed mitochondrial dynamics, increasing the fission marker dynamin-1-like protein 1 (DRP1) and decreasing the fusion markers mitofusins (MFNs) and optic atrophy protein 1 (OPA). This condition increased intracellular ROS production, and reduced mitochondrial membrane potential, which can probably be associated with THC-related reduced fetal growth (Walker et al. 2020).

In a neonatal rat model of iron-overload, CBD has proven to exert neuroprotective effects, preventing cognitive decline by preserving synaptic function in the hippocampus and cortex. This protection is attributed to the downregulation of caspase-3 under iron-induced stress, as well as the modulation of DRP1 and OPA1, which are involved in mitochondrial fission and fusion, respectively. CBD reverses the effects of iron on the decrease of DRP1 gene expression (da Silva et al. 2014).

As mentioned above, THC has been shown to adversely affect mitochondrial respiration and increase oxidative stress (Quenardelle et al. 2025; Charles et al. 2024), which has been linked to a higher risk of cerebrovascular disease associated with marijuana use. Several factors can modulate THC-induced mitochondrial dysfunction, including the concentration of THC in the specific cannabis strains, as it has been observed in behavioral outcomes in animal models (Egashira et al. 2008). Interestingly, this mitochondrial dysfunction may be attenuated by the development of THC tolerance, caused by repeated, chronic drug administration that leads to a progressive decrease in the physiological effects (Abood et al. 1993; McKinney et al. 2008). The molecular mechanism responsible for cannabinoid tolerance includes downregulation and desensitization of the CB1 receptor, which reduce responsiveness to subsequent stimulation (Martin et al. 2004).

However, CBD exhibits a complex, multifaceted influence on mitochondrial function, as evidenced by numerous studies in vivo and in vitro employing a range of doses and routes of administration (Drummond-Main et al. 2023; Puighermanal et al. 2024). These findings reveal that the effects of CBD on mitochondrial dynamics, bioenergetics, and oxidative stress are context-dependent, varying according to cell type, experimental conditions, and pharmacological parameters. This diversity in the effects of phytocannabinoids on mitochondrial function is not well understood. One potential explanation is biased agonism, a phenomenon where an agonist selectively activates downstream signaling pathways over others, thereby promoting specific intracellular effects (Wootten et al. 2018). Biased agonism at cannabinoid receptors is well-established (Patel et al. 2021).

Although, the regular use of cannabis, especially with high-THC strains, may induce mitochondrial dysfunction, the presence of CBD and the development of receptor tolerance may influence these effects, underscoring the significance of considering specific compounds and usage patterns when estimating their impact on mitochondrial function.

In addition, different studies suggest an involvement of cannabinoid ligands in mitochondrial biogenesis under pathological conditions (Bai et al. 2017; Liu et al. 2022). Specifically, the activation of the CB1R by ACEA induces the expression of the transcription factor Nrf1 and its target genes, promoting mitochondrial biogenesis in a cerebral ischemia model (Bai et al. 2017). In this study, the synthetic cannabinoid ACEA increases the number and volume of mitochondria in the rat cortex after reperfusion, indicating the modulation of the biogenesis of this organelle by ACEA. In line with this observation, agonism of the CB1R promotes the expression of Nrf1, Tfam, and COX IV in cortical neurons, acting as downstream targets phosphorylated by GSK-3β (Bai et al. 2017). Interestingly, pharmacological inhibition of GSK-3β with TDZD-8 conveys similar effects as ACEA in the expression of the later mentioned mitochondrial proteins. Contrasting results were observed with the PI3K inhibitors wortmannin and LY294002, which downregulated the expression of Nrf1, Tfam, and COX IV in the presence of ACEA, rescinding the protective function of ACEA in different mitochondrial metabolism parameters, such as a decreased ATP production, lower mitochondrial membrane potential, increased mPTP opening, and oxidative markers (Bai et al. 2017). This suggests that the phosphorylation of GSK-3β through the PI3K/AKT cascade is crucial for the preservation of mitochondrial function and neuronal viability by ACEA in the context of cerebral ischemia/reperfusion.

Similarly, in a subarachnoid hemorrhage (SAH) model, the CB1R is upregulated from six up to 72 h after the injury, a pattern that is mirrored by the Nrf1 protein, denoting a compensatory mechanism early on after the hemorrhage (Liu et al. 2022). The modulation of Nrf1 and other downstream pathways following CB1R activation by ACEA is indispensable for the protection conferred by this cannabinoid, given that the silencing of Nrf1 and antagonism of CB1R inhibited the protective effects regarding neurofunctional outcomes, such as balance, spontaneous activity, side stroking, vibrissae touch, limb symmetry, lateral turning, forelimb walking and climbing (Liu et al. 2022). In addition to promoting mitochondrial biogenesis, ACEA induces the PINK1/Parkin pathway involved in mitophagy, regulating the expression of autophagy-related genes TOMM20 and LC3, in a CB1R and Nrf1-dependent manner (Liu et al. 2022). Altogether, the control of mitophagy and mitochondrial biogenesis by ACEA improves mitochondrial morphology, oxidative stress markers, and the size of the injury in a SAH model.

The regulation of mitophagy by cannabinoids in the brain appears to be influenced by factors such as age and is associated with memory decline. Specifically, the reduced expression of the CB1 receptor in the hippocampus diminishes the expression of mitophagy markers (i.e., serine-65 phosphorylated ubiquitin and PINK1 activity) and leads to the accumulation of aberrant mitochondria with abnormal morphology during aging (Kataoka et al. 2020; Zhi et al. 2019). This accumulation adversely affects the bioenergetic capacity and the redistribution from axon to soma (Kataoka et al. 2020). Altogether, this translates into age-dependent synaptic deficiencies in hippocampal neurons.

Other mitochondrial proteins that act as downstream targets of the CB1 receptor include MFN2, a fusion protein located in the outer mitochondrial membrane (OMM). The accumulation of MFN2 has been shown to convey protective effects in ischemic and hypoxic environments (Peng et al. 2018). Moreover, cannabidiol alleviates neuronal death and mitochondrial damage in an oxygen-glucose deprivation/reperfusion (OGD/R) model, through the disruption of Parkin’s binding to MFN2, decreasing its proteasomal degradation. Consequently, the induction of MFN2 by cannabidiol diminishes endoplasmic reticulum (ER) stress markers (GRP78, p-IRE1α, and p-eIF2α), and enhances mitophagy (Xu et al. 2023).

In summary, the regulation of the ECS influences mitochondrial homeostasis, which requires a balance among processes such as biogenesis, fission, and fusion, and mitophagy. These events work in unison to maintain mitochondrial biogenetics and support cell viability.

6 The mitochondrial CB1 receptor

Cannabinoid receptors are typically found in the plasma membrane; however, their presence in intracellular compartments, such as the mitochondrial membrane of different cell types, including neurons, has been reported in the last decade (Bénard et al. 2012; Hebert-Chatelain et al. 2016). Recent findings have demonstrated the involvement of cannabinoid receptors and their respective downstream signaling pathways in the interaction between cannabinoids and mitochondria. Furthermore, as mentioned above, cannabinoids have been established as modulators of mitochondrial processes, such as energy balance and metabolism (Bénard et al. 2012). This is in accordance with the already known role of CB1R in energy homeostasis (Silvestri and Di Marzo 2013). Specifically, it was demonstrated that activation of mitochondrial CB1R (mtCB1R) by exogenous or endogenous cannabinoids downregulates mitochondrial respiration and ATP production (Fišar et al. 2014).

6.1 Discovery of intracellular CB1R

CB1 receptors, like other GPCRs, were originally identified in the plasma membrane, where it is regulated by extracellular signals, and transform them into intracellular signaling cascades. However, existing literature on GPCRs has predominantly focused on water-soluble ligands, which cannot traverse the cell membrane. In contrast, cannabinoid receptor ligands, including endocannabinoids, synthetic cannabinoids, and phytocannabinoids are primarily lipid-based compounds that can easily permeate the plasma membrane through lateral diffusion, thereby accessing intracellular compartments. Additionally, the cell can actively internalize endocannabinoids such as AEA via specific transporters (Di Marzo 2011). The ability of these molecules to access the cell challenges the conventional paradigm that functional GPCRs are exclusively located at the plasma membrane. Notably, a significant proportion of CB1 receptors are predominantly expressed intracellularly, having been identified in intracellular vesicles (Leterrier et al. 2004), endosomal/lysosomal compartments (Rozenfeld and Devi 2008), and more recently at the mitochondrial membrane of both presynaptic and somatodendritic compartments of neurons (Bénard et al. 2012), as well as in astrocytes (Gutiérrez-Rodríguez et al. 2018; Jimenez-Blasco et al. 2020), and peripheral tissue (Mendizabal-Zubiaga et al. 2016; Pagano Zottola et al. 2022).

The study of Bénard et al. (2012) challenged the prevailing view that GPCRs, specifically the CB1R, are strictly localized in the plasma membrane. Utilizing techniques such as immunogold electron microscopy, the authors demonstrated the presence of CB1R in the mitochondria of hippocampal neurons from wild-type mice, but not in CB1R knockout mice. They further characterized the expression of functional downstream effectors of G-protein signaling, thereby opening pathways for studying the intracellular mechanisms regulated by cannabinoids in both physiological and pathological contexts. Consequently, while some receptor-mediated effects of cannabinoids may be derived from the activation of the CB1R in the plasma membrane, others may involve cannabinoids interacting with receptors located within intracellular compartments, representing a novel approach to understanding the mechanism of action of cannabinoids.

6.2 Evolutionary significance of mtCB1R in the brain and peripheral tissue

The CB1R in peripheral tissues is predominantly expressed in the mitochondria of striated muscle cells and cardiomyocytes. In skeletal muscle, the mtCB1R is present in the gastrocnemius and rectus abdominis (Mendizabal-Zubiaga et al. 2016). The activation of mtCB1R in muscle cells appears to modulate oxidative stress by regulating pyruvate metabolism and decreasing mitochondrial respiration (Mendizabal-Zubiaga et al. 2016). Interestingly, mtCB1R expression in striated muscle is higher than in the brain, possibly due to the elevated energy demand of this tissue. This suggests a role in regulating the oxidative capacity of muscle fibers and may influence the adaptive shift between oxidative (slow-twitch) and glycolytic (fast-twitch) fiber phenotypes in response to metabolic demands.

Additionally, the mtCB1R expressed in epididymal white adipose tissue (eWAT) has been reported to negatively regulate complex I-dependent oxygen consumption through the cAMP-PKA pathway (Pagano Zottola et al. 2022). This mechanism facilitates the accumulation of fat by diminishing the capacity of adipocytes to expend energy. These findings support the idea that mtCB1R represents an evolutionarily conserved mechanism for maintaining cellular and systemic energy homeostasis, linking the ECS and the overall metabolic health (Shin et al. 2009; Rakotoarivelo et al. 2021).

In neurons, the localization of CB1R in both the plasma membrane and mitochondria is not redundant, but rather reflects a more sophisticated and layered control mechanism. Each receptor pool serves a distinct, yet complementary, function. The plasma membrane CB1R mediates the canonical ECS signaling that induces a rapid, retrograde inhibition of the neurotransmitter released resulting from the endocannabinoids derived postsynaptically (Howlett 2004). Therefore, these receptors are responsible for a fast regulation of synaptic communication. In contrast, the mtCB1R exerts slower, metabolic-level control by influencing mitochondrial function, therefore regulating the long-term energy supply of the synapse. This modulation is essential for processes such as long-term potentiation (LTP) and long-term depression (LTD) that depend on sustained metabolic changes (Bénard et al. 2012; Hebert-Chatelain et al. 2016). This is particularly crucial in neurons, which are the most energy-demanding cells in the body, requiring a high amount of ATP to maintain their membrane potential and support rapid synaptic transmission and plasticity (Magistretti and Allaman 2018). In practice, mtCB1R could function as a metabolic rheostat, modulating the overall capacity of the synapse to function over time, and ensuring that the energetic cost of synaptic signaling is met by the metabolic capacity of the cell.

Although the mtCB1 is not exclusively neuronal, this cell type may have been the first to adopt its expression, possibly due to its specific energy constraints. Indeed, this dual system may enable neurons to respond rapidly not only to immediate signaling needs, but also to adapt their long-term metabolic state to changing demands, a hallmark of evolutionary success. It is possible that this mechanism could have been later adopted by the peripheral tissues for the control of systemic energy balance. Thus, the mtCB1 represents an evolutionary conserved strategy arising from the need for a metabolic checkpoint, aligning energy expenditure and storage to coordinate both local signaling and systemic energy homeostasis.

6.3 Localization and function of mtCB1R

In the brain, mtCB1R is present in several structures, including the hippocampus, prefrontal cortex, piriform cortex, olfactory bulb, and nucleus accumbens (Gómez-Sotres et al. 2024; Gutiérrez-Rodríguez et al. 2018; Jimenez-Blasco et al. 2020). This receptor is involved in modulating bioenergetic processes and cellular respiration, including the decrease of oxygen consumption, ATP production, and the disruption of mitochondrial membrane potential (Bénard et al. 2012). These alterations are associated with the negative behavioral effects of cannabinoids such as catalepsy (Soria-Gomez et al. 2021), impaired cognitive performance (Hebert-Chatelain et al. 2016), and diminished social interaction (Jimenez-Blasco et al. 2020). In this context, mtCB1R participates in neurotransmission and synaptic plasticity, contributing to motor control, as well as memory and learning processes in the hippocampus (Hebert-Chatelain et al. 2016). Furthermore, they play a key role in the regulation of food intake through hypothalamic pro-opiomelanocortin (POMC) neurons (Koch et al. 2015), and influence social behavior and nociception via the striatonigral circuit (Soria-Gomez et al. 2021). In addition to neuronal expression, mtCB1R can also be found in astrocytes, where they regulate glucose metabolism (Jimenez-Blasco et al. 2020), lateral synaptic plasticity (Serrat et al. 2022), and cognitive adaptation in response to stress (Gómez-Sotres et al. 2024).

6.4 Signaling pathways triggered upon mtCB1R activation

Long before the identification of mtCB1R, various studies investigated the effects of cannabinoids on mitochondrial bioenergetics. One of the first studies, conducted by Chari-Bitron and Bino (1971) investigated the effect of THC on rat liver mitochondria, where it promoted alterations on the organization of mitochondria in a concentration-dependent manner, which caused an increase in the ATPase activity. Additionally, THC has been shown to inhibit NADH-oxidase activity in rat brain and heart mitochondria, disrupting the electron transport chain at both the cytochrome c site and the amytal-sensitive site (Bartova and Birmingham 1976). While these effects were primarily attributed to the ability of lipid cannabinoids to induce structural modifications in the mitochondrial membrane properties, recent findings make it possible to hypothesize that the observed mitochondrial alterations resulted from the activation of mtCB1 receptors, rather than from non-specific modifications of the mitochondrial membrane.

The mtCB1R, like their counterparts in the plasma membrane, are coupled to Gαi/o proteins, which signal the downstream inhibition of PKA activity through the decrease in cAMP concentrations. Hebert-Chatelain et al. (2016) identified that the inhibition of the Gαi subunit with pertussis toxin (PTX) prevented the cannabinoid-induced reduction in the mitochondrial cAMP levels, PKA, and complex I activity, thereby indicating that mtCB1R serve as GPCRs. More specifically, the complex I subunit NDUFS2 (NADH dehydrogenase [ubiquinone] iron-sulfur protein subunit 2) is phosphorylated by PKA, which is reliant on mtCB1R signaling, and its deletion nullifies the effect of the agonist WIN55,212–2 on cellular respiration. Interestingly, the deletion of the first 22 amino acids of the CB1R protein (DN22-CB1) sequence is involved in the exclusion of the receptor from the mitochondria, so the mutants only express functional CB1R in the plasma membrane. In this regard, under physiological conditions, the effects of cannabinoids in mitochondrial metabolism are mostly dependent on the signaling mediated by the mtCB1R, given that non-permeable CB1R agonists are unable to exert their inhibitory action on mitochondrial respiration as opposed to lipophilic cannabinoid ligands (Bénard et al. 2012).

Similar studies have demonstrated that anandamide and the synthetic agonist WIN55,212–2 exert a full or partial inhibitory effect on the mitochondrial respiratory rate in the brain, whereas the pharmacological blockade of the CB1R with the membrane-permeant antagonist AM251 mitigates the impact of cannabinoids on the decreased activity of mitochondrial complexes (Fišar et al. 2014). Furthermore, PKA located on the mitochondrial outer membrane (OMM) can interact with various anchoring proteins (AKAPs), thereby regulating not only energetic processes but also mitochondrial morphology and trafficking under physiological conditions (Dagda and Das Banerjee 2015). AKAPs interact with the cytoskeleton by binding to microtubules and actin (Diviani and Scott 2001), facilitating the growth of dendritic arbors and the axonal transport of various cargo. Given that the activation of mtCB1R can modify PKA activity, cannabinoid ligands may play a role in the regulation of mitochondrial dynamics beyond metabolism functions, including organelle trafficking, mitochondrial structure, and plasticity of axonal and dendritic structures.

In addition to the functional machinery associated with GPCR activation, it has been suggested that the synthesis and degradation of endocannabinoids are intricately linked to mitochondrial function in a regulatory manner. Bénard et al. (2012) measured the activity of monoacylglycerol lipase (MAGL) in purified mitochondrial samples. The inhibition of MAGL by JZL195 resulted in an increased level of 2-AG, which was inversely correlated with a reduced respiration rate in wild-type mitochondria, but not in CB1R knockouts. This finding indicates that mitochondria possess the necessary machinery to promote endocannabinoid accumulation, which can directly activate mtCB1R. Altogether, the evidence suggests that the activation of mtCB1R by cannabinoids reduces cAMP levels, which in turn decreases the oxygen consumption rate through the cannabinoid-dependent inhibition of electron transport chain activity, thereby resulting in diminished electron transfer from cytochrome c to oxygen.

6.5 Regulation of mitochondrial complexes by mtCB1 receptors

Maintaining the balance between the pro-oxidant and antioxidant stimuli in the brain is essential for preserving synaptic transmission and plasticity (Beckhauser et al. 2016). In this context, elevated ROS levels are associated with cognitive decline in neurodegenerative diseases (Zhang et al. 1999). Notably, mitochondria are well recognized as one of the primary sources of cellular ROS, with mitochondrial complex I being identified as a major contributor to mitochondrial ROS (mROS) generation in both neurons and astrocytes, a process that is regulated by its assembly into super complexes (Lopez-Fabuel et al. 2016).

The mitochondrial complex I forms an L-shaped structure that protrudes into the matrix, which consists of a peripheral arm formed by two functional modules: an electron input module (N-module), responsible for the oxidation of NADH, and an output module (Q-module), that carries out the electron transfer to ubiquinone; both modules possess redox-active cofactors critical for the respiratory chain (Mimaki et al. 2012). The N-module contains different NADH-dehydrogenase-ubiquinone (NDU) subunits: NDUFV1, NDUFV2, and NDUFS1, involved in proton translocation and ubiquinone binding (Vogel et al. 2007).

Complex I is a critical target during ischemia/reperfusion-induced mitochondrial injury, leading to the exacerbation of ROS resulting from the dysfunction in complex I as well as the release of reduced flavin into the mitochondrial matrix, which reacts with oxygen to produce superoxide and hydrogen peroxide (Kahl et al. 2018). These pro-oxidant stimuli derived from the autooxidation of the reduced flavin upon the reintroduction of oxygen may be responsible for the transient burst in ROS synthesis during the initial stages of reperfusion (Hernansanz-Agustín et al. 2017; Pell et al. 2016).

As shown in Figure 2, the mtCB1R modulates the activity of mitochondrial complexes through their phosphorylation by PKA, modifying the proton gradient from the mitochondrial matrix to the intermembrane space and disturbing the mitochondrial membrane potential. Recent evidence indicates that cannabinoids, specifically HU210 and THC, mediate a reduction in mROS by destabilizing the complex I subunit NDUFS4-PM, through mtCB1R signaling (Hebert-Chatelain et al. 2016). By disrupting the integrity of the complex I N-module, cannabinoids can interfere with the binding of O2 molecules responsible for receiving electrons from NADH(H+), thus suppressing ROS generation (Wirth et al. 2016). Nonetheless, cAMP has also been shown to promote the NADH-ubiquinone oxidoreductase activity of complex I which prevents the formation of mROS through the cAMP-dependent protein kinase (Bellomo et al. 2006). This represents an interesting mechanism by which cannabinoids modulate redox homeostasis. In this regard, the usage of antioxidants against mROS and the changes in mROS triggered by mtCB1 receptor activation might provide useful insights on the physiological and pathological functions modulated by cannabinoids acting at the mitochondrial level.

Figure 2: The inhibition of PKA activity mediated by mtCB1R regulates the function of mitochondrial complex I through its decreased phosphorylation, leading to a reduction in the mitochondrial respiratory chain and ROS production. Created in BioRender. Cerdán-Centeno (2025b) https://BioRender.com/rdhjlpa.
Figure 2:

The inhibition of PKA activity mediated by mtCB1R regulates the function of mitochondrial complex I through its decreased phosphorylation, leading to a reduction in the mitochondrial respiratory chain and ROS production. Created in BioRender. Cerdán-Centeno (2025b) https://BioRender.com/rdhjlpa.

On the other hand, astrocytes also exhibit a destabilization of complex I following mtCB1R stimulation. Jimenez-Blasco et al. (2020) found that the membrane-permeable CB1R agonists THC and HU210 altered the glucose metabolism in mouse astrocytes and affected their social activity. These alterations comprise the reduction in the expression of the subunits NDUFS1 and NDUFV2, which are components of the complex I N-module, a site responsible for the oxidation of NADH(H+). Under these conditions other mitochondrial complexes remain unaffected. Interestingly, the mitochondrial targets of PKA phosphorylation induced by mtCB1R activation differ between astrocytes and neurons: in astrocytes, this activation leads to reduced phosphorylation of the NDUFS4 subunit, whereas neurons experience a decrease in NDUFS2 phosphorylation (Hebert-Chatelain et al. 2016; Jimenez-Blasco et al. 2020). Therefore, differential destabilization of the mitochondrial complexes according to the cell type represents an important regulatory mechanism under different conditions.

The destabilization of mitochondrial complex I through the activation of the mtCB1R could also have implications in the context of reverse electron transport (RET), a condition implicated in ROS production during reperfusion via the accumulation of succinate (Chouchani et al. 2014). In this sense, mild pharmacological attenuation of complex I activity with OXPHOS uncouplers such as FCCP decreases mitochondrial membrane potential. Thus, the electron transport chain operates at full capacity, abolishing RET (Hernansanz-Agustín et al. 2017). In this regard, inhibition of complex I with rotenone, in addition to the usage of the complex II inhibitor, 3-nitropropionic acid (3-NP), leads to a significant decrease in the mitochondrial reduction capacity, which is partially abolished with the usage of anandamide and WIN55,212–2 through the stimulation of the mtCB1. Interestingly, the preservation of mitochondrial function by these cannabinoids in the presence of 3-NP requires the integral functioning of complex I, despite the molecule acting at complex II, as shown by higher levels of protection in the absence of rotenone (Maya-López et al. 2024). Altogether, cannabinoids act via the mtCB1 to modulate the assembly of complex I as well as the activity of mitochondrial dehydrogenases in both physiological and pathogenic contexts, which provides a novel potential mechanism of mitochondrial protection.

6.6 Modulation of intracellular calcium levels by the mtCB1 receptor

The disruption of calcium homeostasis is a critical factor in initiating cell death associated with neurodegeneration processes. Previous studies have indicated that cannabinoids can modulate cytoplasmic calcium concentrations in neurons via a CB1R-dependent mechanism (Liu et al. 2009; Pulgar et al. 2022). It has been proposed that CB1R activation regulates NMDA-induced calcium increase through the activation of inositol triphosphate receptor (IP3R) signaling pathways (Liu et al. 2009). In astrocytes, the activation of the CB1R increases intracellular calcium levels, facilitating the mobilization of calcium from internal reservoirs via the activation of phospholipase-C (PLC). This process serves as a conduit between neuron-astrocyte communication through the release of gliotransmitters (Navarrete and Araque 2008).

Mitochondrial cannabinoid receptors have also been proposed to regulate intracellular calcium. In a study by Serrat et al. (2022) in astrocytes, it was found that mtCB1R are involved in calcium regulation and are implicated in lateral synaptic potentiation. In this context, the increase in cytosolic calcium concentrations induced by cannabinoids is mediated by the endoplasmic reticulum (ER) via the IP3 receptors, while the mitochondrial calcium uniporter (MCU) modulates calcium levels within the mitochondrial matrix (Serrat et al. 2022). Interestingly, soluble adenylyl cyclase activity is not involved in the regulation of calcium responses to cannabinoids. Instead, AKT activation leads to phosphorylation of the mitochondrial calcium uptake protein 1 (MICU1), a subunit essential for proper MCU function (Serrat et al. 2022). The MCU not only plays a role in the calcium uptake once it is activated by mtCB1R, but its function is also necessary for astrocyte-neuron signaling. While cannabinoid treatment leads to a rise in the calcium levels in astrocytes, this is not specifically modulated by mtCB1R, but CB1R present in the plasma membrane may participate as well (Serrat et al. 2022).

The control of calcium influx through the MCU could constitute an alternate mechanism by which cannabinoids modulate mitochondrial metabolism, independent of the activity of the sAC enzyme (Serrat et al. 2022). The driving force of the MCU is related to the negative membrane potential resulting from the electron transport chain. Therefore, the Ca2+ uptake is electrogenically driven by the voltage present across the inner mitochondrial membrane. Thus, anomalies in the respiratory chain decrease the Ca2+ transfer and negatively impact ATP production (Visch et al. 2004). In addition, alterations in the intramitochondrial calcium levels trigger a decrease in ATP synthesis, considering that three matrix dehydrogenases (pyruvate dehydrogenase, α-ketoglutarate, and isocitrate-dehydrogenases) are dependent on this ion (Rizzuto et al. 2012). These Ca2+-sensitive dehydrogenases increase NADH availability and modify the flow of electrons down the respiratory chain, which ultimately has repercussions on the formation of ATP (Jouaville et al. 1999).

Interestingly, mROS production is modulated by intracellular calcium levels, with ROS increasing after treatment with high concentrations of Ca2+ and Na+, as a result of sustained NMDA receptor stimulation (Dykens 1994). Under these conditions, the inhibition of complex I and III by rotenone and antimycin prevents the NMDA-induced ROS production (Dugan et al. 1995), indicating that both calcium-mediated uncoupling of the electron transport chain and mitochondrial complex dysfunction contribute to the onset of oxidative stress during excitotoxic damage. Therefore, it can be hypothesized that the activation of the mtCB1 receptor, which attenuates complex I activity, might directly influence the formation of mROS and ATP in response to calcium influx, a relevant mechanism for the study of pathologies involving excitotoxicity.

7 mtCB1R and cognitive processes: learning and memory

The effects of mtCB1R activation on physiological processes have been primarily studied in the context of memory performance, where cannabinoid-induced metabolic alterations affect synaptic transmission (Djeungoue-Petga and Hebert-Chatelain 2017). Indeed, alterations in energy supply resulting from mtCB1R stimulation impact neurotransmitter release by modulating Ca2+ levels, ATP production, and redox homeostasis (Hebert-Chatelain et al. 2016). This phenomenon is particularly relevant in processes such as depolarization-induced suppression of inhibition (DSI), which is initiated by an increase in postsynaptic Ca2+ concentrations and contributes to the regulation of endocannabinoid synthesis following the intensity of the depolarizing stimuli (Kano et al. 2009). This aligns with the observation showing that a prolonged depolarization period of 5 sec in pyramidal neurons induces significant inhibitory postsynaptic currents (eIPSCs). This response can be inhibited by AM281, a membrane-permeable CB1R antagonist, but not by hemopressin, which is a cell-impermeable antagonist (Bénard et al. 2012).

Although mtCB1R influences mitochondrial metabolism by reducing the activation of mitochondrial complex I via PKA, cannabinoid ligands do not exhibit similar effects on DSI as other molecules that irreversibly inhibit OXPHOS through binding to mitochondrial complexes. Bénard et al. (2012) demonstrated that while rotenone, a potent complex I inhibitor, can enhance DSI amplitude during short depolarization periods in the postsynaptic neuron, it does not affect eIPSCs in the absence of depolarizing stimuli nor alter inhibitory neurotransmission. Given that rotenone significantly suppresses mitochondrial function during short depolarization periods, it is plausible that it interferes with mtCB1R-mediated modulation of DSI.

Among the various effects associated with cannabinoid-dependent mitochondrial inhibition, Hebert-Chatelain et al. (2016) identified that cannabinoids can impair novel object recognition (NOR) due to alterations in the synaptic activity of hippocampal neurons. This impairment is influenced by the deterioration of mitochondrial mobility, respiration, and, more critically, ATP production. The reduction in excitatory postsynaptic potentials (EPSP) induced by the potent CB1R agonist HU-210 depends on the activation of PKA. This was corroborated by the pharmacological inhibition of PKA using KH7, which demonstrates a blockade of the effects mediated by HU-210 without altering synaptic transmission itself. This study indicates that higher cognitive functions such as learning, and memory are compromised by a depletion of the energy reserves within the brain.

In addition to the effects of the mtCB1R on memory and learning, other studies have explored a potential interaction between corticosterone and mtCB1R regulation of NOR. These studies suggest that, unlike exogenous cannabinoids, the inhibition of mitochondrial metabolism does not appear to significantly affect memory consolidation and retrieval (Bénard et al. 2012; Hebert-Chatelain et al. 2016). Instead, corticosterone stimulates the mobilization of endocannabinoid to activate mtCB1R, regulating Ca2+ currents through the phosphorylation of the mitochondrial calcium uniporter (MCU) (Skupio et al. 2023). Furthermore, noradrenergic and GABAergic neurons play a significant role in the impairment of NOR induced by exogenous corticosterone through the alterations in mitochondrial calcium levels. Given that mtCB1R activation enhances mitochondrial calcium uptake, Skupio et al. (2023) demonstrate an interaction between calcium concentrations and the recognition of novel stimuli. In this context, corticosterone influences memory consolidation, particularly involving noradrenergic neurons in the locus coeruleus. During the processes of memory retrieval, there is a reduction in the amplitude of calcium signals in hippocampal GABAergic neurons when confronted with a novel object. This event is impaired by the stimulation of mtCB1R. Importantly, mtCB1R is essential for corticosterone to exert its effects on NOR, affecting both the consolidation and retrieval processes.

8 The neuroprotective implications of the mtCB1R

Blocking molecular pathways associated with neuronal death is crucial for reducing neurological dysfunction in acquired and degenerative brain diseases. The ECS regulates oxidative stress, inflammation, and cellular death (Duncan et al. 2024). The mtCB1R is upregulated following brain injury, with increased CB1R protein levels observed in the mitochondrial fractions of mice and cultured neurons within 24 h of post-TBI (Xu et al. 2016). Similar results were observed in mice with I/R injury and neurons exposed to OGD (Ma et al. 2015). Treatment with ACEA, a CB1R agonist, significantly raised mtCB1R protein levels and improved cell viability while reducing LDH release and neurological impairment in I/R-injured mice. These effects were blocked by AM251, a cell-permeable CB1R antagonist, but not by hemopressin a non-permeable CB1R antagonist (Ma et al. 2015). These results indicate that the neuroprotective properties of ACEA during brain injury are mediated by mtCB1R.

The mechanisms of mtCB1R-mediated neuroprotection are not fully understood. Xu et al. (2016) found that mtCB1R stimulation with THC reduced glucose and pyruvate levels while increasing lactate levels, effects that were reversed by AM251 but not by hemopressin, a non-permeable CB1R antagonist. This stimulation also reduced apoptosis in neurons, although it had a dual effect on mitochondria from injured neurons, where HU-210 decreased cAMP, PKA activity, and mitochondrial complex I activity, leading to ATP reduction and increased apoptosis. Despite this, mtCB1R activation was linked to protein kinase B (AKT) accumulation in neuronal mitochondria, enhancing the AKT/complex V pathway, which increased ATP levels and decreased the release of cytochrome c and apoptosis-inducing factors. The authors conclude that mtCB1R activation during TBI has a dual effect on mitochondrial metabolism and apoptosis (Xu et al. 2016).

In a study by Cai et al. (2017), it was shown in rats subjected to brain ischemia that the neuroprotective effects of the HU-210 were mediated by preservation of the mitochondrial membrane potential and the activity of the respiratory chain complexes, as well as by attenuating ROS production and the mPTP opening (Cai et al. 2017). Additionally, inhibiting the mPTP opening contributes to ACEA neuroprotective effects in neuronal cultures and mice with bilateral common carotid artery occlusion (BCCAO) (Ma et al. 2018). ACEA also prevented mitochondrial swelling in purified mitochondria subjected to a Ca2+-induced injury model (Ma et al. 2015). The mtCB1R contributes to neuroprotection, but its role in mitochondrial homeostasis leads to a dual effect on neurons (Figure 3). The mechanisms of mtCB1R activation following neuronal damage are not well understood.

Figure 3: In response to neuronal damage, the mtCB1R plays a dual role in mitochondria function and dynamics and can promote neuronal death or survival. Cerdán-Centeno (2025c) https://BioRender.com/0vizq1d.
Figure 3:

In response to neuronal damage, the mtCB1R plays a dual role in mitochondria function and dynamics and can promote neuronal death or survival. Cerdán-Centeno (2025c) https://BioRender.com/0vizq1d.

9 Future directions

Given the limited understanding of the ECS in mitochondrial activity, it is necessary to investigate further the role of cannabinoids in mitochondrial function during physiological and pathological conditions. In addition, it is essential to evaluate the involvement of mtCB1R in excitotoxicity, a process associated with calcium deregulation and mitochondrial dysfunction, which occurs in several acquired and neurodegenerative brain disorders. The use of transgenic mice lacking mtCB1R provides a valuable tool for elucidating the specific role of this receptor in the brain, both in health and disease.

10 Conclusions

Mitochondria play a critical role in neuronal development and survival. In both degenerative and acquired brain diseases, alterations in mitochondrial activity may contribute to neuronal death. The mtCB1R regulates the activity of the respiratory complexes, modulates ATP and ROS production, and influences intracellular Ca2+ levels. Although the reports are limited, the stimulation of the mtCB1R during brain injury appears to exert dual effects on mitochondrial activity, promoting either neuroprotection or neuronal death depending on the context. Nevertheless, the involvement of mtCB1R in brain injury appears promising for the identification of possible molecular targets for therapeutic intervention. Furthermore, the mtCB1R has been implicated in cognitive processes such as learning and memory. Additional studies are needed to clarify the specific role of mtCB1R in the brain under both physiological and pathological conditions.

Corresponding author: Julio Morán, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ap. Postal 70-253, 04510, Cd. De México, México, E-mail:
Ari Misael Martínez-Torres and Keyla Tamara Cerdán-Centeno contributed equally to this work.

Funding source: Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México

Award Identifier / Grant number: IN216422

Award Identifier / Grant number: IN224425

Acknowledgments

K.T.C.C. is a doctorate student at the Posgrado en Ciencias Biológicas, UNAM. K.T.C.C. was also granted a fellowship from Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCyT) (CVU: 1248950). C.N.M. is a CONAHCyT (now Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI) postdoctoral fellow (I1200/224/2021)). Images created with BioRender.com.

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: A.M.T.M. and K.T.C.C. had the idea for the article. All authors wrote the first draft of the manuscript, commented on previous versions of the manuscript, and critically revised the work. JM raised funds and contributed to the writing and review of the manuscript. All authors read and approved the last version of the manuscript.

  4. Use of Large Language Models, AI and Machine Learning Tools: Not applicable.

  5. Conflict of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest.

  6. Research funding: This work was supported by the Dirección General de Asuntos del Personal Académico, UNAM (DGAPA-PAPIIT, UNAM) [Grant IN216422 and IN224425].

  7. Data availability: Not applicable.

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Received: 2025-06-27
Accepted: 2025-10-03
Published Online: 2025-10-22

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

https://doi.org/10.1515/revneuro-2025-0086
Keywords for this article
cannabinoids; mtCB1; endocannabinoid system; mitochondrial dysfunction; neurodegeneration
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