ATP Synthase C-Subunit-Deficient Mitochondria Have a Small Cyclosporine A-Sensitive Channel, but Lack the Permeability Transition Pore

Permeability transition (PT) is an increase in mitochondrial inner membrane permeability that can lead to a disruption of mitochondrial function and cell death. PT is responsible for tissue damage in stroke and myocardial infarction. It is caused by the opening of a large conductance (∼1.5 nS) channel, the mitochondrial PT pore (mPTP). We directly tested the role of the c-subunit of ATP synthase in mPTP formation by measuring channel activity in c-subunit knockout mitochondria. We found that the classic mPTP conductance was lacking in c-subunit knockout mitochondria, but channels sensitive to the PT inhibitor cyclosporine A could be recorded. These channels had a significantly lower conductance compared with the cyclosporine A-sensitive channels detected in parental cells and were sensitive to the ATP/ADP translocase inhibitor bongkrekic acid. We propose that, in the absence of the c-subunit, mPTP cannot be formed, and a distinct cyclosporine A-sensitive low-conductance channel emerges. [Display omitted] •Deletion of the c-subunit leads to loss of the mPTP channel•C-subunit KO mitochondria contain a CSA-sensitive channel•The c-subunit KO channel has lower conductance compared to mPTP•The c-subunit KO channel is sensitive to ANT inhibitors Neginskaya et al. report that c-subunit-deficient mitochondria contain a CSA-sensitive channel. This channel is much smaller compared with the wild-type permeability transition pore and is sensitive to inhibitors of adenine nucleotide translocase. This work highlights the importance of the c-subunit in forming the permeability transition pore.