The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging
Suzanne Angeli, Anna Foulger, Manish Chamoli, T. Harshani Peiris, Akos A. Gerencser, Azar Asadi Shahmirzadi, Julie K. Andersen, Gordon J. Lithgow
Abstract
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 (UPR mt ). Pharmacological or genetic inhibition of the mPTP inhibits the UPR mt 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/UPR mt nexus may contribute to aging and age-related diseases and how inhibition of the UPR mt may be protective under certain conditions.