Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice.
Cyclophilin D (which is encoded by the Ppif gene) is a mitochondrial matrix peptidyl-prolyl isomerase known to modulate opening of the mitochondrial permeability transition pore (MPTP). Apart from regulating necrotic cell death, the physiologic function of the MPTP is largely unknown. Here we have shown that Ppif(-/-) mice exhibit substantially greater cardiac hypertrophy, fibrosis, and reduction in myocardial function in response to pressure overload stimulation than control mice. In addition, Ppif(-/-) mice showed greater hypertrophy and lung edema as well as reduced survival in response to sustained exercise stimulation. Cardiomyocyte-specific transgene expression of cyclophilin D in Ppif(-/-) mice rescued the enhanced hypertrophy, reduction in cardiac function, and rapid onset of heart failure following pressure overload stimulation. Mechanistically, the maladaptive phenotype in the hearts of Ppif(-/-) mice was associated with an alteration in MPTP-mediated Ca(2+) efflux resulting in elevated levels of mitochondrial matrix Ca(2+) and enhanced activation of Ca(2+)-dependent dehydrogenases. Elevated matrix Ca(2+) led to increased glucose oxidation relative to fatty acids, thereby limiting the metabolic flexibility of the heart that is critically involved in compensation during stress. These findings suggest that the MPTP maintains homeostatic mitochondrial Ca(2+) levels to match metabolism with alterations in myocardial workload, thereby suggesting a physiologic function for the MPTP.
Elrod
John W
JW
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio 45229, USA.
Wong
Renee
R
Mishra
Shikha
S
Vagnozzi
Ronald J
RJ
Sakthievel
Bhuvana
B
Goonasekera
Sanjeewa A
SA
Karch
Jason
J
Gabel
Scott
S
Farber
John
J
Force
Thomas
T
Brown
Joan Heller
JH
Murphy
Elizabeth
E
Molkentin
Jeffery D
JD
D000375:Aging / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009200:Myocardial Contraction
D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D021983:Cyclophilins; D002118:Calcium