The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging.
Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPRmt). Pharmacological or genetic inhibition of the mPTP inhibits the UPRmt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging. Our findings reveal how an mPTP/UPRmt nexus may contribute to aging and age-related diseases and how inhibition of the UPRmt may be protective under certain conditions.
['Angeli|Suzanne|S|0000-0002-6229-9648', 'Foulger|Anna|A|', 'Chamoli|Manish|M|0000-0003-0339-7894', 'Peiris|Tanuja Harshani|TH|', 'Gerencser|Akos|A|', 'Shahmirzadi|Azar Asadi|AA|', 'Andersen|Julie|J|', 'Lithgow|Gordon|G|0000-0002-8953-3043']
D000375:Aging D000818:Animals D017173:Caenorhabditis elegans D008928:Mitochondria D051336:Mitochondrial Membranes D000083162:Mitochondrial Permeability Transition Pore D056811:Unfolded Protein Response
mitochondrial permeability transition pore mitochondrial unfolded protein response aging F-ATP synthase C. elegans c-subunit cell biology oscp/atp-3