The capacity for oxidative metabolism is a fundamental property of the differentiated state that varies widely among animal cells and tissues. Differences in respiratory function in both normal cells and a variety of cellular pathologies are reflected in the number, size, and morphology of mitochondria as well as in the expression of respiratory gene products. A fundamental issue is how nuclear and mitochondrial genetic systems are coordinated to meet cellular energy demands. Because of the limited coding capacity of the mitochondrial genome, oxidative function relies upon nuclear genes for most of the respiratory subunits and all of the gene products required for the transcription and replication of mitochondrial DNA (mtDNA).
Characterization of mammalian genes encoding the respiratory cytochromes has led to the discovery of nuclear respiratory factors (NRFs). These nuclear transcriptional activators promote the expression of genes encoding respiratory subunits as well as key components of the mtDNA transcription and replication machinery. Recent findings have established that one of these proteins, NRF-1, responds to cellular signaling pathways through post-translational modifications and through its specific interaction with transcriptional co-activators. Such mechanisms allow the relay of regulatory signals to the mitochondria via the activation of NRF-1 target genes within the nucleus. In this way NRFs and associated regulatory proteins may serve to integrate nuclear and mitochondrial genetic systems to accommodate cellular demands for respiratory energy.
Our long-term objectives are to further define the molecular interactions and physiological functions of transcriptional activators and co-activators involved in the nuclear control of the respiratory apparatus. Current work in the lab combines molecular and biochemical approaches with the development of cellular and transgenic models to understand in vivo regulatory pathways and mechanisms.
Publications:
Vercauteren, K., Pasko, R.A., Gleyzer, N., Marino, V.M. and Scarpulla, R.C. PGC-1-related coactivator (PRC): immediate early expression and characterization of a CREB/NRF-1 binding domain associated with cytochrome c promoter occupancy and respiratory growth. Mol. Cell. Biol. 26, 7409-7419 (2006).
Scarpulla, R.C. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol. Rev. 88(2), 611-638 (2008).
Vercauteren, K., Gleyzer, N. and Scarpulla, R.C. PGC-1-related coactivator complexes with HCF-1 and NRF-2β in mediating NRF-2(GABP)-dependent respiratory gene expression. J. Biol. Chem. 283, 12102-12111 (2008).
Scarpulla, R.C. Nuclear control of respiratory chain expression by nuclear respiratory factors (NRFs) and PGC-1-related coactivator (PRC). Ann. NY Acad. Sci. 1127, 321-334 (2008).
Vercauteren, K., Gleyzer, N. and Scarpulla, R.C. Short hairpin RNA-mediated silencing of PRC (PGC-1-Related Coactivator) results in a severe respiratory chain deficiency associated with the proliferation of aberrant mitochondria. J. Biol. Chem. 284, 2307-2319 (2009).
