Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death

Abstract

FOF1-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 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. Why it mattersBedaquiline (BDQ) is the only FDA-approved drug to treat pulmonary multidrug-resistant tuberculosis (TB), caused by the Mycobacterium tuberculosis. BDQ cures TB by specifically targeting mycobacterial ATP synthase and inhibiting ATP production. Recently, BDQ was also reported to bind to mammalian ATP synthase at the interface between the a and c-subunits and to inhibit its catalytic activity. However, the effect of BDQ on ATP synthase leak channel activity has not been explored. Here, we report that BDQ inhibits the ATP synthase c-subunit leak channel (ACLC) activity with an IC50 of [~]24 nM and prevents glutamate-induced neuronal death, suggesting a new therapeutic repurposing of BDQ for treating ACLC-related diseases.