Alexander Tzagoloff

Propagation of mitochondria depends on the expression of a small number of mitochondrial genes and a much larger pool of genetic information resident in nuclear DNA. Current estimates suggest that in the budding yeast Saccharomyces cerevisiae, close to 400 nuclear genes (referred to as PET genes) encode proteins with functions directly relevant to the maintenance of respiring mitochondria. While the functions of the mitochondrial gene products are well understood, the same cannot be said of the nuclear counterparts. An unexpectedly large proportion of PET genes have turned out to selectively affect the synthesis of individual respiratory complexes such as cytochrome oxidase and the proton translocating ATPase complex. In addition to coding for known subunit polypeptides of these heteroligomeric enzymes, PET genes govern processing of mitochondrial pre-mRNAs, translation of the mature mRNAs, and a host of post- translational events crucial for the production of the final active complexes. The functions of nuclear gene products involved in promoting late steps in assembly of the respiratory chain complexes, ensuing translation, import, and membrane insertion of all the constituents are the main focus of ongoing studies in our laboratory.

Valnot, I., von Kleist-Retzow, J.-C., Barrientos, A., Gorbatyuk, M., Rustin, P., Tzagoloff, A., Rotig, A., and Munnich, A. (1999) A mutation in the human COX10 gene for heme A:farnesyl transferase causes cytochrome oxidase deficiency, Hum. Mol. Genet. 9, 1245-1249.

Hell, K., Tzagoloff, A., Neupert, W., and Stuart, R. (2000) Cox20p, a novel yeast protein involved in the maturation of cytochrome oxidase subunit 2. J. Biol. Chem. 275, 4571-4578.

Souza, R. L., Green-Willms, N. S., Fox, T. D., Tzagoloff, A., and Nobrega, F. G. (2000) Cloning and characterization of COX18, a Saccharomyces cerevisiae PET gene required for the assembly of cytochrome oxidase., J. Biol. Chem. 275, 14898-14902.

Leonhard, K., Guiard, b., Pellechia, G., Tzagoloff, A., Neupert, W., and Langer, T. (2000) Membrane protein degradation by AAA-proteases in mitochondria involves substrate extraction and can occur from either membrane surfaces. Mol. Cell 5, 629-638.

Paul, M.-F., Barrientos, A., and Tzagoloff, A. (2000) A single amino change in subunit 6 of the yeast mitochondrial ATPase suppresses a null mutation in ATP10. J. Biol. 275, 29238-29243.

Barros, M. H., Carlson, C. G., Glerum, D. M., and Tzagoloff, A. (2001) Involvement of mitochondrial ferredoxin and Cox15p in hydroxylation of heme O. FEBS Lett. 492, 133-138.

de Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Benayoun, E., Chretien, D., Kadhom, N., Lombes, A., Ogier de Baulny, H., Niaudet, P., Rustin, P., Munnich, A., and Rotig, A. (2001) Mutations in BCS1, a mitochondrial respiratory chain assembly gene, are responsible for the complex III deficiency of patients with fatal tubulopathy and liver failure. Nature Genet. 29, 57-60.

Barrientos, A., Barros, M. H., Valnot, I., Rotig, A., Rustin, P., and Tzagoloff, A. (2001) Cytochrome oxidase in health and disease" Gene, in press.