Regulation of mitochondrial biogenesis in cardiac and skeletal myocytes has important physiological consequences. In cardiomyocytes, mitochondrial content increases proportionately with contractile elements during ventricular hypertrophy induced by pressure or volume overload. In skeletal fibers, mitochondrial content can be regulated independently of contractile proteins as an adaptive response to exercise training or continuous nerve stimulation. In this proposal we seek to increase understanding of the biochemical mechanisms that regulate mitochondrial biogenesis in mammalian striated muscle cells. Results obtained in the initial phase of this project direct further research toward two classes of cellular events as possible rate-limiting steps for mitochondrial biogenesis: replication of mitochondrial DNA, and transcription of nuclear genes encoding mitochondrial proteins. The first set of specific aims of this renewal seeks to identify biochemical details of the regulation of mitochondrial DNA synthesis in muscle cells. We shall determine whether changes in the concentration or functional activity of specific proteins currently known to be involved in replication of mitochondrial DNA are evoked by stimuli that alter mitochondrial biogenesis in muscle cells. In addition, we plan to determine which of the specific steps known to be required for replication of the mitochondrial genome are altered. A second set of specific aims seeks to identify biochemical details of the transcriptional regulation of nuclear genes that encode mitochondrial proteins. We plan to identify nuclear proteins that bind to regulatory elements within such genes, and to test the hypothesis that the concentration and/or functional activity of such regulatory factors is altered by changes in muscle contractile activity. Specific attention will be directed to nuclear genes encoding inner membrane (beta F1ATPase) and matrix proteins (citrate synthase) important for oxidative metabolism, as well as genes that encode proteins involved in mitochondrial DNA replication, such as DNA polymerase gamma.
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