| Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease. | |
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MedLine Citation:
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PMID: 23320803 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 which result in complex I deficiency are the most common OXPHOS disorders in humans. To determine if 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; Ndufs6gt/gt, 32% activity and Ndufs6gt/+, 83% activity compared to WT 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 oxidised 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 upregulation 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. 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. |
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Authors:
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Josephine M Forbes; Bi-Xia Ke; Tuong-Vi Nguyen; Darren C Henstridge; Sally A Penfold; Adrienne Laskowski; Karly Sourris; Lukas N Groschner; Mark E Cooper; David R Thorburn; Melinda Coughlan |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-16 |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: - ISSN: 1557-7716 ISO Abbreviation: Antioxid. Redox Signal. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Baker IDI Heart & Diabetes Institute, Glycation and Diabetes, Melbourne, Victoria, Australia; josephine.forbes@bakeridi.edu.au. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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