title: CypD(-/-) hearts have altered levels of proteins involved in Krebs cycle, branch chain amino acid degradation and pyruvate metabolism.
abstract: Cyclophilin D (CypD) is a mitochondrial chaperone that has been shown to regulate the mitochondrial permeability transition pore (MPTP). MPTP opening is a major determinant of mitochondrial dysfunction and cardiomyocyte death during ischemia/reperfusion (I/R) injury. Mice lacking CypD have been widely used to study regulation of the MPTP, and it has been shown recently that genetic depletion of CypD correlates with elevated levels of mitochondrial Ca(2+). The present study aimed to characterize the metabolic changes in CypD(-/-) hearts. Initially, we used a proteomics approach to examine protein changes in CypD(-/-) mice. Using pathway analysis, we found that CypD(-/-) hearts have alterations in branched chain amino acid metabolism, pyruvate metabolism and the Krebs cycle. We tested whether these metabolic changes were due to inhibition of electron transfer from these metabolic pathways into the electron transport chain. As we found decreased levels of succinate dehydrogenase and electron transfer flavoprotein in the proteomics analysis, we examined whether activities of these enzymes might be altered. However, we found no alterations in their activities. The proteomics study also showed a 23% decrease in carnitine-palmitoyltransferase 1 (CPT1), which prompted us to perform a metabolomics analysis. Consistent with the decrease in CPT1, we found a significant decrease in C4/Ci4, C5-OH/C3-DC, C12:1, C14:1, C16:1, and C20:3 acyl carnitines in hearts from CypD(-/-) mice. In summary, CypD(-/-) hearts exhibit changes in many metabolic pathways and caution should be used when interpreting results from these mice as due solely to inhibition of the MPTP.
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Menazza
authors.forename: Renee
authors.initials: R
authors.lastname: Wong
authors.forename: Tiffany
authors.initials: T
authors.lastname: Nguyen
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D000818:Animals; D002952:Citric Acid Cycle; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption; D011422:Propionates / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*
chemical_list: D000597:Amino Acids, Branched-Chain; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; C000631446:PPIF protein, mouse; D011422:Propionates; D020543:Proteome; D019289:Pyruvic Acid; D021983:Cyclophilins