Cannabinoid-mediated targeting of mitochondria on the modulation of mitochondrial function and dynamics

Abstract

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.

Keywords: Calcium homeostasis; Cannabinoid receptors; Endocannabinoidome; Mitochondrial fission and fusion; Mitophagy; Substances of abuse.