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.
Highlights
Mitochondria are cytoplasmic double-membrane-delimited organelles of variable size, with a diameter between 0.5 and 5 μm, which are organized in a dynamic network [1] and are responsible of the aerobic production of ATP by the oxidative phosphorylation system (OXPHOS)
OXPHOS catalyzes the oxidation of fuel molecules and the concomitant synthesis of ATP via five complexes located in the inner mitochondrial membrane (IMM), which is highly folded into cristae
Through its contacts with the F1 α3β3 hexamer and the peripheral stalk, oligomycin-sensitivity conferring protein (OSCP) ensures the structural and functional coupling between FO and F1, which is necessary for ATP synthesis, and modulates the enzyme complex and is the target of inhibitors and interactors, including cyclophilin D (CyPD)
Summary
Mitochondria are cytoplasmic double-membrane-delimited organelles of variable size, with a diameter between 0.5 and 5 μm, which are organized in a dynamic network [1] and are responsible of the aerobic production of ATP by the oxidative phosphorylation system (OXPHOS). The OSCP (oligomycin-sensitivity conferring protein) subunit of ATP synthase appears to play a unique role, being the site of interaction of cyclophilin (CyP) D, a matrix protein that favors PTP opening, as will be discussed below. The majority of mitochondrial proteins is encoded in the nucleus and post-translationally imported into the organelle by a complex protein-import machinery [11], some subunits of the OXPHOS (13 in humans) are encoded by the mitochondrial genome (mtDNA), which is present in several copies per organelle and is exclusively maternally inherited. The novel function of ATP synthase in PTP formation makes this picture much more complex, considering the role played by PTP and by its dysregulation in a variety of diseases characterized by altered cell death, which include ischemia-reperfusion injury of the heart and brain, muscular dystrophies, neurodegeneration and cancer [5,17]
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