The Unique Cysteine of F-ATP Synthase OSCP Subunit Participates in Modulation of the Permeability Transition Pore

Abstract

Highlights d C141 of OSCP subunit of F-ATP synthase regulates the mitochondrial PTP d Oxidation of OSCP C141 sensitizes the PTP to the inducing effect of diamide d CyPD exerts a protecting effect by masking OSCP C141 d Genetic ablation of CyPD sensitizes PTP to diamide

Defining the molecular mechanisms of the mitochondrial permeability transition through genetic manipulation of F-ATP synthase

“…Whether the PTP originates from a Ca 2+ -dependent conformation of F-ATP synthase is the matter of debate. Evidence in favor is based on reconstitution experiments from mitochondria of various origins 21 – 24 , on knockdown of subunit c 25 , 29 , on generation of point mutations that affect specific channel properties 22 , 32 – 37 , and on reconstitution of channel activity from highly purified and fully functional F-ATP synthase from bovine and porcine hearts 38 , 39 . Evidence against is provided by persistence of a CsA-sensitive PT after genetic ablation of subunit c and of constituents of the F-ATP synthase peripheral stalk 26 – 28 .…”

“…In yeast, absence of the “dimerization” subunits e and g, and of the N-terminal segment of subunit b 30 , which closely interacts with subunit g 31 , dramatically decreases both size of the PTP and channel conductance of F-ATP synthase 32 . Furthermore, point mutations that do not affect either assembly of the enzyme complex or ATP synthesis did cause specific changes in the channel properties of the PTP 22 , 32 – 37 . Finally, highly purified F-ATP synthase preparations displayed the features expected of the PTP in electrophysiological experiments 38 , 39 .…”

Modulation and Pharmacology of the Mitochondrial Permeability Transition: A Journey from F-ATP Synthase to ANT

“…The molecular consequence of C141 oxidation is still unclear, although we hypothesized that OSCP homodimers might form between F-ATP synthases of adjacent cristae, leading to a conformational change of the enzyme that could favor the transition toward pore formation. Site-directed mutagenesis in yeast did not provide compelling clues on the involvement of other conserved thiols (those located in subunits α, γ, and c) [119], although the participation of cysteines present uniquely in the mammalian enzyme cannot be ruled out. These findings suggest that other PTP-related proteins, such as ANT, might participate in the PTP modulation by oxidation together with the F-ATP synthase through its OSCP C141.…”

“…This subunit not only represents a binding site for CyPD, but also possesses a critical His (H135) that mediates the effect of pH on the PTP [118]. Furthermore, we recently reported that the unique OSCP Cys (C141), which is in proximity to the H135, is involved in the modulation of the PTP by oxidants [119]. In particular, this thiol which actively responds to DIA and mitoparaquat and modulates pore opening appears to be masked by the binding of CyPD, which exerts a protective role.…”

The mitochondrial permeability transition pore: an evolving concept critical for cell life and death

“…This protein is able to modulate ATP synthase activity, causing it to decrease when mitochondrial CypD is anchored and to regulate mPTP opening (and cell death) via its C141 and H112 residues. These residues respectively affect the sensitivity of the pore to oxidation and its dependence on H + binding (Antoniel et al, 2018;Carraro et al, 2020).…”