MOLECULAR GENETICS OF MAMMALIAN CYTOCHROME C OXIDASE

Wayne State University, Detroit MI

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Abstract

DESCRIPTION: Cytochrome c oxidase, the terminal protein of the electron transport chain, is composed in mammals of thirteen subunits, three encoded by mitochondrial DNA and ten by nuclear DNA. At least three of these nuclear subunits occur in more than one molecular form (isoforms), the products of separate genes. The proposed experiments will provide insights into the cellular function of these isoforms, which may be related to both ontogenetic development and cellular physiology. In addition, isoform expression has been implicated in human neuromuscular disease. This project will focus on three genes, already isolated, that encode two subunits, COX VIIa and COX VIIc. Subunit VIIa displays a heart/muscle-specific isoform (H) and an isoform (L) expressed in all tissue. A second subunit, VIIc, appears to have a single expressed form in all tissues. The specific aims are to (1) characterize the core promoter interactions in the COX7AL, COX7AH, and COX7C genes; (2) determine the roles of promoter-distal sequences and factors in regulatory events that occur at the COX7AL, COX7AH, and COX7C core promoters by (a) identifying new regulatory sites that are core promoter distal, (b) identifying new regulatory sites and factors by application of yeast one-and two-hybrid technologies, and (c) determining the effect of new regulatory factor binding on events at the core promoter, and also the effect of distal DNA sequences per se; and (3) elucidating promoter function in cell development and differentiation. This project fits into the longer term objectives of deducing the role of the nuclear-encoded subunits and the mechanisms used to regulated oxidative function, and applying this knowledge to the study of nuclear genes in mitochondrial disease.