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Deficiency in mitochondrial complex i Activity Due to Ndufs6 gene trap insertion induces renal disease

Citation

Forbes, JM and Ke, B-X and Nguyen, T-V and Henstridge, DC and Penfold, SA and Laskowski, A and Sourris, KC and Groschner, LN and Cooper, ME and Thorburn, DR and Coughlan, MT, Deficiency in mitochondrial complex i Activity Due to Ndufs6 gene trap insertion induces renal disease, Antioxidants and Redox Signaling, 19, (4) pp. 331-343. ISSN 1523-0864 (2013) [Refereed Article]

Copyright Statement

Copyright 2013 Mary Ann Liebert, Inc.

DOI: doi:10.1089/ars.2012.4719

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.

Item Details

Item Type:Refereed Article
Keywords:antioxidant, cystatin C, kidney injury molecule 1, reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone), albuminuria, animal experiment, animal tissue, article, chronic disease, controlled study, disorders of mitochondrial functions
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell metabolism
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Henstridge, DC (Mr Darren Henstridge)
ID Code:133341
Year Published:2013
Web of Science® Times Cited:18
Deposited By:Health Sciences
Deposited On:2019-06-24
Last Modified:2019-07-22
Downloads:0

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