Molecular Genetics of Mammalian Cytochrome c Oxidase

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Cytochrome c oxidase, the terminal protein of the electron transport chain, is composed in mammals of thirteen subunits, three encoded by mitochondrial DNA and the remainder by nuclear DNA. In addition to the fact that the function is unknown for all ten of the nuclear-encoded subunits, a second level of complexity has been introduced by the finding that at least three, probably more, and possibly even all of these nuclear subunits occur in more than one cellular form (isoforms). We will (1) focus on two subunits of cytochrome c oxidase, VIIa and VIIc, that are present as isoforms in order to (a) isolate and characterize cDNAs for each isoform, and (b) determine the mechanism by which these isoforms arise by examining their transcripts and the organization of their coding regions in the genome; (2) seek insights into the role of these isoforms by examining the distribution of their transcripts in various adult bovine tissues, and in tissues taken from several different developmental stages; and (3) investigate the regulation of these and other cytochrome c oxidase subunits for which we have probes by observing their stoichiometry in cultured bovine cells, particularly after perturbation of the synthesis of specific subunits with antisense transcripts. How a complex protein such as cytochrome c oxidase is correctly assembled is obscure. Even more mysterious are the mechanisms involved in the synchronous regulation of gene expression, particularly when some are located on the nuclear genome and others on the organelle genome, so that the proper ration of subunits to be assembled results. The results of this study will give us little more insight into that complex process.