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SHR Neuro Cancer Cardio Lipid Metab Microb

Forbes, JM; Ke, BX; Nguyen, TV; Henstridge, DC; Penfold, SA; Laskowski, A; Sourris, KC; Groschner, LN; Cooper, ME; Thorburn, DR; Coughlan, MT.
Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease.
Antioxid Redox Signal. 2013; 19(4):331-343 Doi: 10.1089/ars.2012.4719
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Co-authors Med Uni Graz: Groschner Lukas
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Abstract:: Aims: 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. Results: Ndufs6 mice had a partial renal cortical complex I deficiency; Ndufs6(gt/gt), 32% activity and Ndufs6(gt/+), 83% activity compared with wild-type mice. Both Ndufs6(gt/+) and Ndufs6(gt/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 Ndufs6(gt/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 F-2t, and up-regulation of antioxidant defence. Juvenile Ndufs6(gt/gt) mice also exhibited signs of early renal impairment with increased urinary Kim-1 excretion and elevated circulating cystatin C. Innovation: 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. Conclusion: 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.
Find related publications in this database (using NLM MeSH Indexing): Adenosine Triphosphate - metabolism; Animals -; Antioxidants - metabolism; Electron Transport Complex I - deficiency; Kidney Diseases - genetics; Mice -; Mice, Knockout -; Mitochondrial Diseases - genetics; NADH Dehydrogenase - genetics; Reactive Oxygen Species - metabolism; Superoxide Dismutase - metabolism