Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 180, Issue -, Pages 33-51Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2022.01.001
Keywords
Cannabinoid; Mitochondrial dysfunction; Oxytosis; ferroptosis; Neurodegenerative disease; Aging; Neurotherapeutics; Antioxidant defense; AMPK
Funding
- Paul F. Glenn Center for Biology of Aging Research at the Salk Institute Fellowship
- National Institutes of Health [R01AG069206, RF1AG054714, R21AG064287]
- NIH-NCI CCSG grant [P30014195]
- NIH [S10OD021815]
- Waitt Foundation
- Chapman Foundation
- Helmsley Charitable Trust
- Shiley Foundation Fellowship
- Bundy Foundation Fellowship
- Shiley-Marcos Alzheimer's Disease Research Center at the University of California, San Diego
- Salk Institute
- Helmsley Center for Genomic Medicine
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The study demonstrates that cannabinol (CBN) can protect nerve cells from oxytosis/ferroptosis by targeting mitochondria and preserving key mitochondrial functions. These protective effects are mediated by promoting endogenous antioxidant defenses and activating AMP-activated protein kinase (AMPK) signaling. This research highlights the potential of mitochondrially-targeted compounds like CBN as novel inhibitors for mitochondrial dysfunction and neurodegenerative diseases.
The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway can be used to identify novel drug candidates for the treatment of age-associated neurodegenerative diseases that act by preserving mitochondrial function. Previously, we identified cannabinol (CBN) as a potent neuroprotector. Here, we demonstrate that not only does CBN protect nerve cells from oxytosis/ferroptosis in a manner that is dependent on mitochondria and it does so independently of cannabinoid receptors. Specifically, CBN directly targets mitochondria and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis. These protective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP-activated protein kinase (AMPK) signaling. Together, our data highlight the potential of mitochondrially-targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction as well as opportunities for the discovery and development of future neurotherapeutics.
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