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Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease.
- Source :
-
Antioxidants & redox signaling [Antioxid Redox Signal] 2013 Aug 01; Vol. 19 (4), pp. 331-43. Date of Electronic Publication: 2013 Mar 01. - Publication Year :
- 2013
-
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.<br />Results: 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.<br />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.<br />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.
- Subjects :
- Adenosine Triphosphate metabolism
Animals
Antioxidants metabolism
Electron Transport Complex I genetics
Kidney Diseases genetics
Mice
Mice, Knockout
Mitochondrial Diseases genetics
NADH Dehydrogenase genetics
Reactive Oxygen Species metabolism
Superoxide Dismutase metabolism
Electron Transport Complex I deficiency
Electron Transport Complex I metabolism
Kidney Diseases metabolism
Mitochondrial Diseases metabolism
NADH Dehydrogenase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-7716
- Volume :
- 19
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Antioxidants & redox signaling
- Publication Type :
- Academic Journal
- Accession number :
- 23320803
- Full Text :
- https://doi.org/10.1089/ars.2012.4719