The mitochondrial ATP synthase is a negative regulator of the mitochondrial permeability transition pore

• DOI: 10.1073/pnas.2303713120
• Publication Date: 2023-12-13T18:31:15Z
• Authors: Ryan Pekson; Felix G. Liang; Joshua L. Axelrod; Jaehoon Lee; Dongze Qin; Andre J. H. Wittig; Victor M. Paulino; Min Zheng; Pablo M. Peixoto; Richard N. Kitsis
• Keywords: MPTP; Mitochondrial apoptosis-induced channel; Mitochondrial matrix

The mitochondrial permeability transition pore (mPTP) is a channel in the inner membrane whose sustained opening response to elevated matrix Ca 2+ concentrations triggers necrotic cell death. molecular identity of mPTP unknown. One proposed candidate ATP synthase, canonical function generate most multicellular organisms. Here, we present mitochondrial, cellular, and vivo evidence that, rather than serving as mPTP, synthase inhibits this pore. Our studies confirm previous work showing persistence HAP1 lines lacking an assembled synthase. Unexpectedly, however, observe that -induced markedly sensitized by loss Further, cells desensitized pharmacological inhibition genetic depletion cis-trans prolyl isomerase cyclophilin D wild-type cells, indicating can modulate through substrates other subunits Mitoplast patch clamping showed conductance was unaffected but still blocked inhibition. Cardiac mitochondria from mice heart muscle engineered deficient also demonstrate sensitization desensitization these exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion vivo. We conclude does not instead negatively regulates