Richard C. Scarpulla, PhD Professor Cell and Molecular Biology Transcriptional Mechanisms of Nucleo-Mitochondrial Interaction in Mammalian Cells Curricula: Cell Biology Developmental Biology Molecular Biology and Genetics E-mail:   rsc248@northwestern.edu

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:

Kelly, D.P. and Scarpulla, R.C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18, 357-368 (2004).

Cam, H., Balciunaite, E., Blais, A., Spektor, A., Scarpulla, R.C., Young, R., Kluger, Y. and Dynlacht, B.D. A common set of gene regulatory networks links metabolism and growth inhibition. Mol. Cell 16, 399-411 (2004).

Gleyzer, N., Vercauteren, K. and Scarpulla, R.C. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol. Cell. Biol. 25, 1354-1366 (2005).

Scarpulla, R.C. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochem. Biophys. Acta 1576, 1-14 (2002).

Huo, L. and Scarpulla, R.C. Mitochondrial DNA instability and periimplantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Mol. Cell. Biol. 21, 644-654 (2001).

Andersson, U. and Scarpulla, R.C. PGC-1-related coactivator: a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol. Cell. Biol. 21, 3738-3749 (2001).

Herzig, R.P., Scacco, S., and Scarpulla, R.C. Sequential Serum-Dependent Activation of CREB and NRF-1 leads to Enhanced Mitochondrial Respiration through the Induction of Cytochrome c. J. Biol. Chem. 275, 13134-13141 (2000).

Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R.C., and Speigelman, B.M. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1, Cell 98, 115-124 (1999).