Deficiency in Mitochondrial Complex I Activity Due toNdufs6Gene Trap Insertion Induces Renal Disease
| Autor: | Karly C. Sourris, Tuong-Vi Nguyen, Josephine M. Forbes, Adrienne Laskowski, Darren C. Henstridge, Lukas N. Groschner, David R. Thorburn, Sally A. Penfold, Melinda T. Coughlan, Mark E. Cooper, Bi-Xia Ke |
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| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Mitochondrial Diseases Physiology Clinical Biochemistry Oxidative phosphorylation Gene mutation urologic and male genital diseases Biochemistry Antioxidants Mice chemistry.chemical_compound Adenosine Triphosphate Internal medicine medicine Renal fibrosis Animals Molecular Biology General Environmental Science Mice Knockout NDUFS6 Gene knockdown Electron Transport Complex I biology Superoxide Dismutase Superoxide NADH Dehydrogenase Cell Biology Endocrinology Mitochondrial respiratory chain Cystatin C chemistry biology.protein General Earth and Planetary Sciences Kidney Diseases Reactive Oxygen Species |
| Zdroj: | Antioxidants & Redox Signaling. 19:331-343 |
| ISSN: | 1557-7716 1523-0864 |
| Popis: | Defects in the activity of enzyme complexes of the mitochondrial respiratory chain are thought to be responsible for several disorders, including renal impairment. Gene mutations that result in complex I deficiency are the most common oxidative phosphorylation disorders in humans. To determine whether an abnormality in mitochondrial complex I per se is associated with development of renal disease, mice with a knockdown of the complex I gene, Ndufs6 were studied.Ndufs6 mice had a partial renal cortical complex I deficiency; Ndufs6gt/gt, 32% activity and Ndufs6gt/+, 83% activity compared with wild-type mice. Both Ndufs6gt/+ and Ndufs6gt/gt mice exhibited hallmarks of renal disease, including albuminuria, urinary excretion of kidney injury molecule-1 (Kim-1), renal fibrosis, and changes in glomerular volume, with decreased capacity to generate mitochondrial ATP and superoxide from substrates oxidized via complex I. However, more advanced renal defects in Ndufs6gt/gt mice were observed in the context of a disruption in the inner mitochondrial electrochemical potential, 3-nitrotyrosine-modified mitochondrial proteins, increased urinary excretion of 15-isoprostane F2t, and up-regulation of antioxidant defence. Juvenile Ndufs6gt/gt mice also exhibited signs of early renal impairment with increased urinary Kim-1 excretion and elevated circulating cystatin C.We have identified renal impairment in a mouse model of partial complex I deficiency, suggesting that even modest deficits in mitochondrial respiratory chain function may act as risk factors for chronic kidney disease.These studies identify for the first time that complex I deficiency as the result of interruption of Ndufs6 is an independent cause of renal impairment. |
| Databáze: | OpenAIRE |
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