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.
Highlights
Peroxisome proliferator-activated receptor ␥ coactivator 1 (PGC-1) ␣ and  are transcriptional regulators of mitochondrial metabolism
Gene regulatory studies demonstrated that the expression of the gene encoding the CL biosynthesis enzyme CDP-diacylglycerol synthase 1, which catalyzes a proximal step in CL synthesis, was downregulated
The CDP-diacylglycerol synthase 1 (Cds1) gene was shown to be a direct target for PGC-1␣ through its coactivating function on the transcription factor ERR␣
Summary
Peroxisome proliferator-activated receptor ␥ coactivator 1 (PGC-1) ␣ and  are transcriptional regulators of mitochondrial metabolism. Peroxisome proliferator-activated receptor ␥ coactivator 1 (PGC-1)-␣ and - serve as inducible transcriptional coregulators of genes involved in mitochondrial biogenesis and metabolism. 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. Gene regulatory studies demonstrated that this abnormal CL phenotype is related to a defect in the PGC-1-mediated transcriptional control of CDP-diacylglycerol synthase (Cds1), an enzyme that catalyzes a critical upstream step in the biosynthesis of CL. Taken together, these results identify a new role for the PGC-1 coactivators in the regulation of PL synthesis relevant to cardiac mitochondrial structure and function
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