Document Detail

Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice.
MedLine Citation:
PMID:  20890047     Owner:  NLM     Status:  MEDLINE    
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.
John W Elrod; Renee Wong; Shikha Mishra; Ronald J Vagnozzi; Bhuvana Sakthievel; Sanjeewa A Goonasekera; Jason Karch; Scott Gabel; John Farber; Thomas Force; Joan Heller Brown; Elizabeth Murphy; Jeffery D Molkentin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-20
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  120     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-05     Completed Date:  2010-11-10     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3680-7     Citation Subset:  AIM; IM    
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MeSH Terms
Aging / metabolism
Calcium / metabolism*
Cardiomegaly / etiology
Cyclophilins / physiology*
Heart Failure / etiology*
Mice, Transgenic
Mitochondria, Heart / metabolism
Mitochondrial Membrane Transport Proteins*
Myocardial Contraction
Grant Support
5F32HL092737/HL/NHLBI NIH HHS; HL62927/HL/NHLBI NIH HHS; HL80101/HL/NHLBI NIH HHS; HL81104/HL/NHLBI NIH HHS; R37 HL028143/HL/NHLBI NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Mitochondrial Membrane Transport Proteins; 0/mitochondrial permeability transition pore; EC 5.2.1.-/Cyclophilins; EC D; SY7Q814VUP/Calcium

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