We report an atomistic molecular dynamics simulation study aimed at clarifying the biophysical basis of a leak-channel function of the c-subunit ring (c-ring) of mitochondrial ATP synthase. The c-ring is the widely known barrel-shaped component of the F o domain. It typically functions as a specific proton transporter and also has been found capable of uncoupling electron transport from ATP synthesis, through charge leakage. Resulting energy inefficiency is associated with neurological pathologies, including developmental delay, autism, and bipolar mood disorder. Electrophysiological characteristics of the c-ring leak channel also resemble characteristics of the enigmatic mitochondrial permeability transition pore (mPTP), a calcium-sensitive regulator of cell death for which the structure has not yet been established. The ATP synthase c-ring is among several candidate structures for the mPTP. A long-term goal of the current work is to identify conformational changes corresponding with leak-channel opening. Here, we take initial strides in that direction by studying the structural dynamics of several 8-subunit c-ring variants, including one resistant to calcium-stimulated mitochondrial permeability transition and one associated with increased cell death upon ischemia-reperfusion injury. Simulations and analysis suggest that mutations at a constriction point along the transmembrane c-ring lumen can regulate charge leakage by favoring or disfavoring continuity of a water column spanning the lumen. While one point mutation in this region appears to promote constitutive formation of a continuous water column (likely a conductive state), adding further mutations associated with mPTP inactivation disrupts the water column and restores a stably nonconductive state. These findings point toward a regulatory basis for c-ring opening and charge leakage and may enable discovery of open structural conformations through further experimental and simulation study.
Pias et al. (Sun,) studied this question.