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Both ANT and ATPase are essential for mitochondrial permeability transition but not depolarization

ABSTRACT: Summary An increase in permeability of the mitochondrial inner membrane, mitochondrial permeability transition (PT), is the central event responsible for cell death and tissue damage in conditions such as stroke and heart attack. PT is caused by the cyclosporin A (CSA)-dependent calcium-induced pore, the permeability transition pore (PTP). The molecular details of PTP are incompletely understood. We utilized holographic and fluorescent microscopy to assess the contribution of ATP synthase and adenine nucleotide translocator (ANT) toward PTP. In cells lacking either ATP synthase or ANT, we observed CSA-sensitive membrane depolarization, but not high-conductance PTP. In wild-type cells, calcium-induced CSA-sensitive depolarization preceded opening of PTP, which occurred only after nearly complete mitochondrial membrane depolarization. We propose that both ATP synthase and ANT are required for high-conductance PTP but not depolarization, which presumably occurs through activation of the low-conductance PT, which has a molecular nature that is different from both complexes. Graphical abstract Highlights • Both ATP synthase and ANT are required for permeabilization, but not depolarization• CSA-dependent depolarization precedes mitochondrial permeabilization• CSA-dependent depolarization is not dependent on ANT or ATP synthase• Mitochondria disappear from holographic images upon membrane permeabilization Molecular biology; Cell biology; Functional aspects of cell biology.

SUBMITTER: Neginskaya M

PROVIDER: S-EPMC9647522 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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