Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency
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 T...
| Hlavní autoři: | , , , , , |
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| Médium: | Článek |
| Jazyk: | English |
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Elsevier
2013-06-01
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| Edice: | Neurobiology of Disease |
| Témata: | |
| On-line přístup: | http://www.sciencedirect.com/science/article/pii/S0969996113000119 |
| _version_ | 1830199077510316032 |
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| author | Stacy L. Hrizo Isaac J. Fisher Daniel R. Long Joshua A. Hutton Zhaohui Liu Michael J. Palladino |
| author_facet | Stacy L. Hrizo Isaac J. Fisher Daniel R. Long Joshua A. Hutton Zhaohui Liu Michael J. Palladino |
| author_sort | Stacy L. Hrizo |
| collection | DOAJ |
| description | 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; TPIsugarkill is a mutant allele with a missense mutation (M80T) that causes phenotypes similar to human TPI deficiency. In this study, the redox status of TPIsugarkill flies was examined and manipulated to provide insight into the pathogenesis of this disease. Our data show that TPIsugarkill 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 TPIsugarkill animals. We hypothesized that TPIsugarkill 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 TPIsugarkill 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 TPIsugarkill 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. |
| first_indexed | 2024-12-18T02:07:02Z |
| format | Article |
| id | doaj.art-9fcd43daaddf4edda99a17be901b98aa |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-18T02:07:02Z |
| publishDate | 2013-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-9fcd43daaddf4edda99a17be901b98aa2022-12-21T21:24:34ZengElsevierNeurobiology of Disease1095-953X2013-06-0154289296Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiencyStacy L. Hrizo0Isaac J. Fisher1Daniel R. Long2Joshua A. Hutton3Zhaohui Liu4Michael J. Palladino5Deparment of Pharmacology & Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA; Department of Biology, Slippery Rock University of Pennsylvania, Slippery Rock, PA 16057, USA; Corresponding author at: 300J Vincent Science Center 1 Morrow Way, Slippery Rock, PA 16057, USA. Fax: +1 724 738 4782.Department of Biology, Slippery Rock University of Pennsylvania, Slippery Rock, PA 16057, USADepartment of Biology, Slippery Rock University of Pennsylvania, Slippery Rock, PA 16057, USADepartment of Biology, Slippery Rock University of Pennsylvania, Slippery Rock, PA 16057, USADeparment of Pharmacology & Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USADeparment of Pharmacology & Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USATriose 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; TPIsugarkill is a mutant allele with a missense mutation (M80T) that causes phenotypes similar to human TPI deficiency. In this study, the redox status of TPIsugarkill flies was examined and manipulated to provide insight into the pathogenesis of this disease. Our data show that TPIsugarkill 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 TPIsugarkill animals. We hypothesized that TPIsugarkill 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 TPIsugarkill 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 TPIsugarkill 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.http://www.sciencedirect.com/science/article/pii/S0969996113000119Oxidative stressRedoxTPI deficiencyTriose phosphate isomeraseGlycolytic enzymopathyDrosophila |
| spellingShingle | Stacy L. Hrizo Isaac J. Fisher Daniel R. Long Joshua A. Hutton Zhaohui Liu Michael J. Palladino Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency Neurobiology of Disease Oxidative stress Redox TPI deficiency Triose phosphate isomerase Glycolytic enzymopathy Drosophila |
| title | Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency |
| title_full | Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency |
| title_fullStr | Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency |
| title_full_unstemmed | Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency |
| title_short | Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency |
| title_sort | early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of tpi deficiency |
| topic | Oxidative stress Redox TPI deficiency Triose phosphate isomerase Glycolytic enzymopathy Drosophila |
| url | http://www.sciencedirect.com/science/article/pii/S0969996113000119 |
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