The oligomycin-sensitivity conferring protein of mitochondrial ATP synthase: emerging new roles in mitochondrial pathophysiology.
The oligomycin-sensitivity conferring protein (OSCP) of the mitochondrial F(O)F1 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 F(O) 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.
Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35121 Padua, Italy. manuela.antoniel@studenti.unipd.it.
Manuela
M
Antoniel
Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35121 Padua, Italy. vgiorgio@bio.unipd.it.
Valentina
V
Giorgio
Department of Biomedical Sciences, University of Udine, p.le Kolbe, 33100 Udine, Italy. federico.fogolari@uniud.it.
Federico
F
Fogolari
Department of Chemistry, Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA. gglick@umich.edu.
Gary D
GD
Glick
Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35121 Padua, Italy. bernardi@bio.unipd.it.
Paolo
P
Bernardi
Department of Food Science, University of Udine, via Sondrio 2/A, 33100 Udine, Italy. Giovanna.lippe@uniud.it.
Giovanna
G
Lippe
D000251:Adenosine Triphosphatases / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D025261:Mitochondrial Proton-Translocating ATPases / Q000032:analysis / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; D021983:Cyclophilins; C020439:oligomycin sensitivity-conferring protein