Role for Peroxisome Proliferator-Activated Receptor. Coactivator-1 in the Control of Mitochondrial Dynamics During Postnatal Cardiac Growth

Rationale: Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional coactivators, peroxisome proliferator-activated receptor coactivator-1 (PGC-1) and PGC-1, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth. The function of PGC-1 coactivators in the heart after birth has been incompletely understood. Objective: Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts in mice. Methods and Results: Conditional gene targeting was used in mice to explore the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts. Marked mitochondrial structural derangements were observed in hearts of PGC-1/-deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion (Mfn1, Opa1) and fission (Drp1, Fis1) was altered in the hearts of PGC-1/-deficient mice. PGC-l was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor on a conserved DNA element. Surprisingly, PGC-1/ deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that PGC-1 coactivators are required for high-level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in the adult heart. Conclusions: These results reveal distinct developmental stage-specific programs involved in cardiac mitochondrial dynamics.