Increased expression and intramitochondrial translocation of cyclophilin-D associates with increased vulnerability of the permeability transition pore to stress-induced opening during compensated ventricular hypertrophy.
Opening of the permeability transition pore (PTP) of mitochondria is a critical permeation event that compromises cell viability and may constitute a factor that participates to the loss of cardiomyocytes in compromised hearts. Mitochondria from hearts with volume overload-induced compensated hypertrophy are more vulnerable to opening of the PTP opening in response to a Ca2+ stress. Several of the factors known to affect PTP opening, including respiratory function, membrane potential, the rate of mitochondrial Ca2+ uptake and endogenous levels of Ca2+ in the mitochondrial matrix, were not altered by volume overload. In contrast, there was an 80% increase in the abundance of the PTP regulating protein cyclophilin-D and a 3.7 fold enhancement of Cyp-D binding to membrane, which all predispose to PTP opening. Mitochondria from volume overloaded animals also displayed elevated rates of production of reactive oxygen species, which may be causally related to both the intramitochondrial translocation of cyclophilin-D and PTP opening, since incubation of cardiac mitochondria with terbutylhydroperoxyde in vitro increased to binding of cyclophilin-D to mitochondrial membranes in a dose-related fashion, except when cyclosporin A (a ligand of cyclophilin D with a known ability to delay PTP opening) was present prior to the addition of terbutylhydroperoxyde. Taken together, these results constitute the first evidence obtained in a pathophysiologic situation that increased abundance of cyclophilin-D within mitochondrial membranes may increase mitochondrial vulnerability to stress, and thus possibly initiate a vicious cycle of cellular dysfunction that may ultimately lead to activation of cell death.
Matas
Jimmy
J
Département de kinésiologie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada H3C 3J7.
Young
Nicholas Tien Sing
NT
Bourcier-Lucas
Céline
C
Ascah
Alexis
A
Marcil
Mariannick
M
Deschepper
Christian F
CF
Burelle
Yan
Y
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000096:biosynthesis*; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D010101:Oxygen Consumption / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
D000081406:Peptidyl-Prolyl Isomerase F; D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D016572:Cyclosporine; D021983:Cyclophilins