title: A role for peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) in the regulation of cardiac mitochondrial phospholipid biosynthesis.
abstract: 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 γ coactivator 1 (PGC-1)-α and -β 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-1α and PGC-1β (PGC-1αβ(-/-)) in adult heart were analyzed. PGC-1αβ(-/-) 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-1αβ-deficient hearts. Gene expression profiling of PGC-1αβ(-/-) 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-1α 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.
authors: From the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827.
authors: Ling
authors: L
authors: Lai
authors: Miao
authors: M
authors: Wang
authors: Ola J
authors: OJ
authors: Martin
authors: Teresa C
authors: TC
authors: Leone
authors: Rick B
authors: RB
authors: Vega
authors: Xianlin
authors: X
authors: Han
authors: Daniel P
authors: DP
authors: Kelly
mesh_terms: D000818:Animals; D056889:Barth Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002798:Diacylglycerol Cholinephosphotransferase / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000235:genetics; D010714:Phosphatidylethanolamines / Q000096:biosynthesis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; C485290:Ppargc1a protein, mouse; D011960:Receptors, Estrogen; D014157:Transcription Factors; C483858:phosphatidylethanolamine; D002798:Diacylglycerol Cholinephosphotransferase
keywords: Cardiac Metabolism; Cardiolipin; Gene Regulation; Heart; Lipidomics; Mitochondria; Phospholipids; Polyunsaturated Fatty Acids; Transcriptional Coregulators