BioProject

The following abstract from the submitted manuscript describes the major findings of this work. More...

The following abstract from the submitted manuscript describes the major findings of this work. The metabolic development of high energy-utilizing organs such as the heart involves mitochondrial proliferation at birth followed by a maturation process during the postnatal period. Conditional gene targeting was used in mice to explore the role of the PPARgamma coactivator 1 (PGC-1) coactivators during postnatal development and in adult heart. Marked mitochondrial derangements were observed in hearts of PGC-1a/b-deficient mice during the postnatal period, including fragmentation and elongation associated with the development of a lethal cardiomyopathy. The expression of multiple genes involved in mitochondrial fusion and fission was downregulated in hearts of PGC-1a/b-deficient mice. PGC-la was shown to activate transcription of the mitofusin 1 (Mfn1) gene by coactivating the estrogen-related receptor a (ERRa) upon a highly conserved element. Surprisingly, PGC-1a/b deficiency did not alter cardiac function or general mitochondrial density and myocyte distribution in adult heart. However, transcriptional profiling and mitochondrial function studies demonstrated that the PGC-1 coactivators are required for full respiratory capacity and high level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial energy transduction and oxidative phosphorylation pathways in adult heart. These results unveil distinct developmental stage-specific transcriptional programs involved in the maturation and maintenance of mitochondria. Overall design: RNA from five PGC-1a-/- and five PGC-1a-/-bf/f/MerCre mice was analyzed. Less...