-ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane and the primary enzyme responsible for ATP production in eukaryotic cells. Nevertheless, it was recently reported to play a prominent role in cell death by forming a large-conductance leak channel in the mitochondrial permeability transition pore (mPTP), making it a promising therapeutic target. Bedaquiline (BDQ), a member of the diarylquinoline class of drugs, was shown to selectively inhibit the catalytic activity of Mycobacterium tuberculosis ATP synthase with no effect on the mammalian enzyme. Here, we report a new role for BDQ as a potent inhibitor of the ATP synthase c-subunit leak channel in mammals. BDQ inhibited the single-channel activity of porcine heart ATP synthase in planar lipid bilayer recordings, inner membrane channel activity of porcine mitochondria in patch-clamp recordings, and prevented glutamate-induced cell death in primary hippocampal neurons. These findings reveal the potential new application of BDQ for treating mPTP-related diseases by targeting the ATP synthase c-subunit leak channel.
Kumar et al. (Fri,) studied this question.