Cytochrome Oxidase Polymorphisms in Aging

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

DESCRIPTION (provided by applicant): Some suspect mitochondria play a role in nervous system senescence and late-onset neurodegenerative disease. Data suggest relevant mechanisms may include inadequate electron transport chain (ETC) function and/or ETC-derived reactive oxygen species (ROS) production. The underlying basis for these ETC-associated events is, however, unknown. The ETC/ATP synthesis apparatus consists of five multimeric protein complexes. Four of them derive subunits from both mitochondrial and nuclear genes. Amino acid-changing polymorphisms are known for many of these genes. This proposal will determine whether ETC gene polymorphisms influence ETC activity and ROS production. It is hypothesized particular nuclear-mitochondrial ETC gene polymorphism combinations produce "efficient" enzyme complexes with robust activity, while other combinations produce "inefficient" enzyme complexes that are less kinetically robust. It is further hypothesized inefficient ETC enzyme complexes will produce more ROS than efficient enzyme complexes. To address this hypothesis, we will (1) determine nucleotide sequences of nuclear cytochrome oxidase (CO) genes from different mtDNA-depleted cell lines, as well as establish how common nuclear CO gene polymorphisms are in the general population; (2) identify how common mtDNA CO gene polymorphisms are in the general population; and (3) create a combination nuclear CO gene knockout-p0 cell line to facilitate replacement with particular mtDNA and nuclear CO gene variants. In humans, the mitochondrial ETC is the only place protein products from two distinct genomes directly interact. Because of genetic variability, multiple subunit combinations are possible. How mitochondrial DNA (mtDNA) and nuclear-derived ETC protein subunits mesh may determine whether an individual's nervous system ages successfully or not. This work could help explain why complex genetic diseases are sometimes associated with mitochondrial dysfunction.