Mitochondria generate the bulk of cellular energy through electron transport and oxidative phosphorylation. They are semiautonomous organelles in that they contain their own DNA genomes (mtDNA), which are replicated, transcribed and translationally expressed within the mitochondrial matrix. However, the coding capacity of mtDNA is limited to 13 protein subunits of the respiratory complexes, and the rRNAs and tRNAs required for their translation. Thus, the nuclear genome provides nearly all of the constituents needed for mitochondrial functions including the maintenance and expression of mtDNA. This arrangement necessitates the interplay of nuclear and mitochondrial genetic systems in meeting cellular energy demands. Both nuclear and mitochondrial genetic lesions, affecting the energy transducing systems of mitochondria, lead to a wide range of human pathologies including various forms of myopathy, cardiomyopathy and central nervous system defects. The overall goal of this proposal is to investigate nuclear regulatory mechanisms that control respiratory chain expression. The main focus is on utilizing biochemical, molecular and genetic approaches to understand the biological functions of nuclear regulatory proteins that control mitochondrial respiratory function. These include the transcriptional activators NRF-1 and NRF-2 that act on the majority of respiratory genes as well as members of the PGC-1 family of coactivators that have been implicated in mitochondrial biogenesis. Emphasis will be placed on PRC, a newly discovered PGC-1 family coactivator that is induced during cell proliferation and coactivates respiratory gene expression by interacting with NRF-I.
The specific aims are: 1) Identify NRF-1 target genes that are activated by PRC and PGC-1 and characterize the molecular determinants of trans-activation. 2) Determine whether the activity or steady-state levels of PRC are altered by agents and conditions known to affect mitochondrial biogenesis. 3) Define the transcription factor specificity of PRC and compare it to that of other PGC-1 family members (PGC-1, PGC-lbeta/PERC). 4) Define structural motifs in PRC that are required for its function. 5) Assess the biological functions of PRC by manipulating its expression in vivo.
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