title: Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency.
abstract: Triose phosphate isomerase (TPI) is responsible for the interconversion of dihydroxyacetone phosphate to glyceraldehyde-3-phosphate in glycolysis. Point mutations in this gene are associated with a glycolytic enzymopathy called TPI deficiency. This study utilizes a Drosophila melanogaster model of TPI deficiency; TPI(sugarkill) is a mutant allele with a missense mutation (M80T) that causes phenotypes similar to human TPI deficiency. In this study, the redox status of TPI(sugarkill) flies was examined and manipulated to provide insight into the pathogenesis of this disease. Our data show that TPI(sugarkill) animals exhibit higher levels of the oxidized forms of NAD(+), NADP(+) and glutathione in an age-dependent manner. Additionally, we demonstrate that mitochondrial redox state is significantly more oxidized in TPI(sugarkill) animals. We hypothesized that TPI(sugarkill) animals may be more sensitive to oxidative stress and that this may underlie the progressive nature of disease pathogenesis. The effect of oxidizing and reducing stressors on behavioral phenotypes of the TPI(sugarkill) animals was tested. As predicted, oxidative stress worsened these phenotypes. Importantly, we discovered that reducing stress improved the behavioral and longevity phenotypes of the mutant organism without having an effect on TPI(sugarkill) protein levels. Overall, these data suggest that reduced activity of TPI leads to an oxidized redox state in these mutants and that the alleviation of this stress using reducing compounds can improve the mutant phenotypes.
authors: Deparment of Pharmacology & Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA. stacy.hrizo@sru.edu
authors: Stacy L
authors: SL
authors: Hrizo
authors: Isaac J
authors: IJ
authors: Fisher
authors: Daniel R
authors: DR
authors: Long
authors: Joshua A
authors: JA
authors: Hutton
authors: Zhaohui
authors: Z
authors: Liu
authors: Michael J
authors: MJ
authors: Palladino
mesh_terms: D000746:Anemia, Hemolytic, Congenital Nonspherocytic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004331:Drosophila melanogaster; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D017354:Point Mutation; D014305:Triose-Phosphate Isomerase / Q000172:deficiency* / Q000235:genetics
chemical_list: D014305:Triose-Phosphate Isomerase