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 (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.
Highlights
As mitochondrial function declines with age, the frequency of the Mitochondrial Permeability Transition Pore (mPTP) increases (Rottenberg and Hoek, 2017)
Loss of oligomycin sensitivity-conferring protein (OSCP)/atp-3 Induces Mitochondrial Permeability Transition Pore Characteristics During Adulthood The opening of the mPTP is characterized by a loss of mitochondrial membrane potential (MMP) as well as an increase in cytosolic Ca2+ and responsiveness to the mPTP inhibitor, Cyclosporin A (CsA)
We observed that a reduction in the abundance of OSCP/atp-3 by RNA interference (RNAi) during adulthood caused a loss of MMP as measured by the mitochondrial dye, Tetramethylrhodamine Methyl Ester (TMRM), while RNAi of other OXPHOS subunits from complex I, IV, and V had no effect on the MMP (Figures 1A, B)
Summary
As mitochondrial function declines with age, the frequency of the mPTP increases (Rottenberg and Hoek, 2017). The mPTP is a pathological channel that forms in the inner mitochondrial membrane in response to excessive cytosolic Ca2+ or high ROS conditions. Sustained opening of the mPTP leads to outer mitochondrial membrane rupture, release of Ca2+ into the cytosol, and cell death (Bernardi and Di Lisa, 2015). Cyclosporin A (CsA), a well-characterized mPTP inhibitor, inhibits the mPTP by binding and sequestering cyclophilin D, a mitochondriallylocalized peptidyl prolyl isomerase that helps catalyze pore formation (Basso et al, 2005; Nakagawa et al, 2005). Genetic inhibition of cyclophilin D protects against mPTP formation (Baines et al, 2005) and CsA has been shown to extend lifespan in C. elegans (Ye et al, 2014). The mPTP appears to be an important modulator of healthspan and lifespan
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