Coordinated regulation of mitochondrial and cellular functions by nuclear receptors

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PROJECT SUMMARY Mitochondria are organelles that generate most of the energy in the cell. There is a gap in our understanding of how specific mitochondrial pathways are regulated to suit tissue-specific function and metabolism. The goal of this proposed research is to fill this knowledge gap and to reveal a previously unrecognized role for a nuclear receptor ERRγ-dependent transcriptional program in kidney physiology and disease. Supported by our extensive preliminary data, we hypothesize that ERRγ contributes to normal kidney function and renal disease by controlling mitochondrial and renal function in cooperation with kidney-specific transcription factors. In Specific Aim 1, we will determine the essential role of ERRγ in maintaining normal mitochondrial and renal function in vivo, using a novel mouse model. We will also investigate whether activation of the ERRγ transcriptional program can improve kidney function in kidney disease models. In Specific Aim 2, we will determine mechanistically how ERRγ regulates renal mitochondrial and functional genes, employing state-of-the-art genomic approaches. Together, these studies will have a significant impact by enhancing our understanding of tissue specific mechanisms for maintaining mitochondrial function, and revealing a novel ERRγ pathway in kidney function and the potential for therapies targeting ERRγ.