The long-range goal of this laboratory is to elucidate the role of mammalian mitochondrial gene products in cellular energy metabolism, organelle biogenesis, and intermediary metabolism. These areas impact human health at several levels including. genetic diseases, developmental biology, and cancer. At present, a major portion of our research focuses upon the role of cytochrome b in electron transport and energy transduction.
The specific aims i nclude: 1) To construct a molecular map of the inhibitor binding domain(s) of the protonmotive cytochrome b of Complex III. 2) To define the role of the cytochrome b inhibitor binding domain(s) in the structure and function of the two redox reaction centers. Particular emphasis will be placed upon testing and refining current models of cytochrome b electron transport. 3) To develop a system of mammalian mitochondrial DNA mutagenesis. 4) To determine the molecular basis of the mitochondrial CAP-R phenotypes and define - at the biochemical level - their effects on mitochondrial protein synthesis and organelle biogenesis. 5) To develop procedures for the direct base sequencing of mammalian mitochondrial DNA or RNA.
|Howell, N; Kubacka, I; Smith, R et al. (1996) Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease. Neurology 46:219-22|
|Howell, N; Kubacka, I; Halvorson, S et al. (1995) Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. Genetics 140:285-302|
|Howell, N; Kubacka, I (1993) Sequence analysis of mitochondrial chloramphenicol resistance mutations in Chinese hamster cells. Mamm Genome 4:271-5|
|Howell, N; Robertson, D E (1993) Electrochemical and spectral analysis of the long-range interactions between the Qo and Qi sites and the heme prosthetic groups in ubiquinol-cytochrome c oxidoreductase. Biochemistry 32:11162-72|
|Howell, N; Kubacka, I; Xu, M et al. (1991) Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet 48:935-42|
|Howell, N; McCullough, D (1990) An example of Leber hereditary optic neuropathy not involving a mutation in the mitochondrial ND4 gene. Am J Hum Genet 47:629-34|
|Howell, N (1990) Glycine-231 residue of the mouse mitochondrial protonmotive cytochrome b: mutation to aspartic acid deranges electron transport. Biochemistry 29:8970-7|
|Raag, R; Poulos, T L (1989) The structural basis for substrate-induced changes in redox potential and spin equilibrium in cytochrome P-450CAM. Biochemistry 28:917-22|
|Howell, N (1989) Evolutionary conservation of protein regions in the protonmotive cytochrome b and their possible roles in redox catalysis. J Mol Evol 29:157-69|
|Howell, N; Lee, A (1989) Sequence analysis of mouse mitochondrial chloramphenicol-resistant mutants. Somat Cell Mol Genet 15:237-44|
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