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OVERVIEW

We study the mitochondrial electron transport chain, with particular attention to cytochrome c oxidase (CcO). CcO is the terminal of the four complexes and catalyzes the transfer of electrons from cytochrome c to oxygen. CcO is composed of 13 subunits: the 3 largest are coded by mitochondrial DNA, the other 10 by nuclear DNA.

 

RESEARCH SUMMARY

Cytochrome oxidase subunit 4-2: The largest subunit encoded by nuclear DNA, CcO4, is found in two forms, each the product of a separate gene. We found the subunit 4 found in all cells (CcO4-1) a number of years ago (Lomax 1984). More recently, a second subunit 4 gene (CcO4-2) was identified that isexpressed in lung and trachea (Hüttemann 2001). Its transcription is stimulated by hypoxia. This stimulation is shown in the figure at right (#1, 2). The square filled bar to the right of the response bars represents a new cis element we have called the oxygen element (Hüttemann 2007); the circles are Sp1-like sites. Mutation of any element reduces promoter response but only mutation of the oxygen element reduces the hypoxic stimulation. Assessment of the enzyme containing about equal amounts of CcO4-1 and 4-2 protein produced twice the activity (turnover number) of a fully 4-1–containing enzyme, suggesting the CcO4-2 enzyme is more active. Our current research directions are to deduce the regulatory pathways by which hypoxia stimulates transcription of CcO4-2, and determining the properties of the enzyme containing the CcO4-2 subunit.

  M.I. Lomax, N.J. Bachman, M. Nasoff, M.H. Caruthers and L.I. Grossman (1984). Isolation and characterization of a cDNA clone for bovine cytochrome c oxidase subunit IV. Proc.  Nat. Acad. Sci. USA 81, 6295-6299.

Molecular evolution of aerobic energy metabolism and the expansion of the neocortex: We observed that many genes of cytochrome oxidase and other members of the electron transport system have been targets of darwinian positive selection in anthropoid primates (Grossman 2004). Sequence comparisons have shown that 9 of the 13 cytochrome oxidase subunits, including the core mitochondrial-encoded ones, have shown marked increases in non-synonymous substitution rate. Increases were also found in subunits of complex III and in cytochrome c. Although the functional gain(s) stemming from these sustitutions is not yet clear, abut one-third of them cluster around the docking site of cytochrome c on cytochrome oxidase; furthermore, their effect is to alter the nature of the docking interaction from the electrostatic one found on non-anthropoid primates, other mammals, and, indeed, all other organisms examined, to the hydrophobic one found in anthropoid primates (Schmidt 2005).

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ADDRESS

Center for Molecular Medicine & Genetics
Wayne State University School of Medicine
3303 Scott Hall
540 E. Canfield Ave.
Detroit, MI 48201
Lab: (313) 577-5219, (313) 577-3418
fax: (313) 577-5218