BPS2026 - In silico mutagenesis reveals residues that modulate ATP synthase transmembrane domain leak channel behavior

In addition to its well-known role in proton transport, the c-subunit ring of ATP synthase also forms a nonselective leak channel. In relation to this function, the c-subunit ring is among several proposed structures for the elusive mitochondrial permeability transition pore (mPTP), an important regulator of mitochondrial swelling and cell death. Prolonged opening of the mPTP is associated with cell death in ischemia-reperfusion injury, as well as in Alzheimer’s and Parkinson’s diseases. The leak channel is also important in other neurological disorders, including Fragile X syndrome and bipolar mood disorder. Yet the molecular components of the mPTP are still unconfirmed. Here, we evaluate the effect of various mutations on the isolated octameric c-subunit ring, using atomistic molecular dynamics simulations. One such mutation found naturally occurring in humans is associated with increased tissue damage due to myocardial infarction. Our simulations indicate that this mutation causes structural changes that align with experimentally based predictions and conductance measurements. We also model a set of mutations associated with resistance to mPTP opening. Introducing these mutations reveals structural characteristics that may be important in gating of the c-subunit ring. This work represents first steps toward understanding how the c-subunit ring of ATP synthase conducts charge across the membrane in its capacity as a leak channel.