Deficiency in Mitochondrial Complex I Activity Due to Ndufs6 Gene Trap Insertion Induces Renal Disease
Publication: Antioxidants & Redox Signaling
Volume 19, Issue Number 4
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; 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. 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. Antioxid. Redox Signal. 19, 331–343.
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Information & Authors
Information
Published In
Antioxidants & Redox Signaling
Volume 19 • Issue Number 4 • August 1, 2013
Pages: 331 - 343
PubMed: 23320803
Copyright
Copyright 2013, Mary Ann Liebert, Inc.
History
Published in print: August 1, 2013
Published online: 29 June 2013
Published ahead of print: 1 March 2013
Published ahead of production: 16 January 2013
Accepted: 15 January 2013
Revision received: 10 January 2013
Received: 26 May 2012
Authors
Author Disclosure Statement
No competing financial interests exist.
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