The Oligomycin-Sensitivity Conferring Protein of Mitochondrial ATP Synthase: Emerging New Roles in Mitochondrial Pathophysiology

Abstract

The oligomycin-sensitivity conferring protein (OSCP) of the mitochondrial FOF1 ATP synthase has long been recognized to be essential for the coupling of proton transport to ATP synthesis. Located on top of the catalytic F1 sector, it makes stable contacts with both F1 and the peripheral stalk, ensuring the structural and functional coupling between FO and F1, which is disrupted by the antibiotic, oligomycin. Recent data have established that OSCP is the binding target of cyclophilin (CyP) D, a well-characterized inducer of the mitochondrial permeability transition pore (PTP), whose opening can precipitate cell death. CyPD binding affects ATP synthase activity, and most importantly, it decreases the threshold matrix Ca2+ required for PTP opening, in striking analogy with benzodiazepine 423, an apoptosis-inducing agent that also binds OSCP. These findings are consistent with the demonstration that dimers of ATP synthase generate Ca2+-dependent currents with features indistinguishable from those of the PTP and suggest that ATP synthase is directly involved in PTP formation, although the underlying mechanism remains to be established. In this scenario, OSCP appears to play a fundamental role, sensing the signal(s) that switches the enzyme of life in a channel able to precipitate cell death.

Mitochondrial Sirtuin Network Reveals Dynamic SIRT3-Dependent Deacetylation in Response to Membrane Depolarization

“…ATP5O has a single histidine residue (H135) that is conserved from yeast to humans (Figure 6I), which has potential to be a pH sensor via its physiologically relevant pK a (Faccenda and Campanella, 2012). This residue is located within the hinge region of ATP5O and lies in one of the lowest surface potential regions on the protein (Antoniel et al, 2014). To probe the role of H135, we mutated this residue to glutamic acid, which cannot be protonated in this pH range, and produced recombinant H135E ATP5O protein (Figure 6D and Figure S6D).…”

Cyclophilin D Promotes Brain Mitochondrial F1FO ATP Synthase Dysfunction in Aging Mice

“…Next, given the primary function of OSCP is to sustain the coupling state of F1FO complex we examined F1FO ATP synthase proton-flow coupling [7, 25] by measuring oligomycin A insensitive respiration on a Clark electrode. Our results showed that nonTg mice displayed remarkably increased oligomycin A insensitive respiration in an age-dependent manner (Fig.…”

Basic Biology of Oxidative Stress and the Cardiovascular System

“…The biochemical data supporting the role of the F 1 −F o ATP synthase is convincing, although its genetic validation in vivo will be complex, given the integral role of this ETC component in mitochondrial ATP synthesis. Additional components of the multimolecular ATP synthase complex are also being studied as potential regulators of the PTP, and hence as potential targets for antinecrotic drug development (48). …”