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Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease.
MedLine Citation:
PMID:  23320803     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  JOURNAL ARTICLE     Date:  2013-1-16
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  -     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Baker IDI Heart & Diabetes Institute, Glycation and Diabetes, Melbourne, Victoria, Australia; josephine.forbes@bakeridi.edu.au.
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