Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics
A B S T R A C T: Mitochondria play a critical role in the regulation of several biological processes (e.g., programmed cell death, inflammation, neurotransmission, cell differentiation). In recent years, accumulating findings have evidenced that cannabinoids, a group of endogenous and exogenous (synthetic and plant-derived) psychoactive compounds that bind to cannabinoid receptors, may modulate mitochondrial function and dynamics. As such, mitochondria have gained increasing interest as central mediators in cannabinoids’ pharmacological and toxicological signatures. Here, we review the mechanisms underlying the cannabinoids’ modulation of mitochondrial activity and dynamics, as well as the potential implications of such mitochondrial processes’ disruption on cell homeostasis and disease. Interestingly, cannabinoids may target different mitochondrial processes (e.g., regulation of intracellular calcium levels, bioenergetic metabolism, apoptosis, and mitochondrial dynamics, including mitochondrial fission and fusion, transport, mitophagy, and biogenesis), by modulating multiple and complex signaling pathways. Of note, the outcome may depend on the experimental models used, as well as the chemical structure, concentration, and exposure settings to the cannabinoid, originating equivocal data. Notably, this interaction seems to represent not only an important feature of cannabinoids’ toxicological signatures, with potential implications for the onset of distinct pathological conditions (e.g., cancer, neurodegenerative diseases, metabolic syndromes), but also an opportunity to develop novel therapeutic strategies for such pathologies, which is also discussed in this review.
Conclusion: Findings thus far suggest that cannabinoids directly or indirectly affect mitochondria functioning through multiple molecular mechanisms. Ultimately, these cannabinoids’ actions may lead to biologically relevant effects on distinct cell lines and tissues, both damaging and protective. It is worth mentioning that cannabinoids are a structurally diverse family of compounds with numerous biological targets. This multiplicity of targets may justify, at least in part, the differentiated or preferential intracellular responses of specific cannabinoids and adds a new layer of complexity to distinguish the effects of cannabinoids through a specific receptor or signalling pathway. Further studies addressing the mechanisms of action of cannabinoids at the mitochondrial level will thus be fundamental to a deeper understanding of their pharmacological activities and risks associated with their misuse. Moreover, the cannabinoids’ modulation of mitochondrial activity and dynamics may be particularly crucial to the toxicological signature of cannabinoids and constitute an opportunity for developing novel therapeutic strategies. In fact, defects in mitochondrial function seem to be a common feature of many human pathological conditions, such as cancer, metabolic syndromes (e.g., obesity) and neurodegenerative diseases (e.g., Charcot-Marie-Tooth disease, Huntington’s disease, and Parkinson’s disease) [176]. The selective targeting of mitochondria through the activation of specific cannabinoid-induced cellular pathways might become an appealing approach to obtain efficient treatments for mitochondria-related diseases in the future. (Source: https://pubmed.ncbi.nlm.nih.gov/36516885/)
(D.I. Commentary: You will find in studying the above excerpt (and full research) that there is, in a number of instances, a dose dependent effect of cannabis shown on for example mitochondrial function.
It is important to understand that to control all they do mitochondria have their own genetic blueprint.
High cannabis doses cause mitochondria dysfunction cellular damage and death. So, this is the problem with having unrestricted upper limits on available cannabis products.
Therefore, simply looking at urine samples, as some pregnancy studies do, only tells you if women have used cannabis in the last month, so we don't separate low from high use and any immediate effect will be lost and we are not getting any real accurate understanding of the impact being made on the mitochondrial function, because there is no, or little data on THC and CBD or other cannabinoid concentrations in the cohort studied.
We are playing with receptors and functions we are only now learning the tip of the iceberg about. A broad-brush estimate of the number of mitochondria per cells is something like 5,000 for heart, around 2000 for liver, but 100,000 or so for oocytes, so these are the cells that can get really disrupted and none of this is good for foetal and human healthy development.)
Also see
- Maternal cannabis use in pregnancy and child neurodevelopmental outcomes
- Self-reported Daily, Weekly, and Monthly Cannabis Use Among Women Before and During Pregnancy
- Cannabis Harms: An Overview of the Known Neurotoxicity and Thalidomide-like Genotoxicity of Cannabis
- Cannabis Use during Pregnancy: Pharmacokinetics and Effects on Child Development.
- Genotoxicity and Neurotoxicity of Cannabis: 66th CND – Vienna UN 2023
