期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 4, 页码 2250-2259出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.523654
关键词
Cardiac Metabolism; Cardiolipin; Gene Regulation; Heart; Mitochondria; Polyunsaturated Fatty Acids; Lipidomics; Phospholipids; Transcriptional Coregulators
资金
- National Institutes of Health [R01 DK045416, R01 HL58493, R01 HL101189]
The energy demands of the adult mammalian heart are met largely by ATP generated via oxidation of fatty acids in a high capacity mitochondrial system. Peroxisome proliferator-activated receptor coactivator 1 (PGC-1)- and - serve as inducible transcriptional coregulators of genes involved in mitochondrial biogenesis and metabolism. Whether PGC-1 plays a role in the regulation of mitochondrial structure is unknown. In this study, mice with combined deficiency of PGC-1 and PGC-1 (PGC-1(-/-)) in adult heart were analyzed. PGC-1(-/-) hearts exhibited a distinctive mitochondrial cristae-stacking abnormality suggestive of a phospholipid abnormality as has been described in humans with genetic defects in cardiolipin (CL) synthesis (Barth syndrome). A subset of molecular species, containing n-3 polyunsaturated species in the CL, phosphatidylcholine, and phosphatidylethanolamine profiles, was reduced in PGC-1-deficient hearts. Gene expression profiling of PGC-1(-/-) hearts revealed reduced expression of the gene encoding CDP-diacylglycerol synthase 1 (Cds1), an enzyme that catalyzes the proximal step in CL biosynthesis. Cds1 gene promoter-reporter cotransfection experiments and chromatin immunoprecipitation studies demonstrated that PGC-1 coregulates estrogen-related receptors to activate the transcription of the Cds1 gene. We conclude that the PGC-1/estrogen-related receptor axis coordinately regulates metabolic and membrane structural programs relevant to the maintenance of high capacity mitochondrial function in heart.
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