Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease

Forbes, Josephine M., Ke, Bi-Xia, Tuong-Vi Nguyen, Henstridge, Darren C., Penfold, Sally A., Laskowski, Adrienne, Sourris, Karly C., Groschner, Lukas N., Cooper, Mark E., Thorburn, David R. and Coughlan, Melinda T. (2013) Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease. Antioxidants and Redox Signaling, 19 4: 331-343. doi:10.1089/ars.2012.4719

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Author Forbes, Josephine M.
Ke, Bi-Xia
Tuong-Vi Nguyen
Henstridge, Darren C.
Penfold, Sally A.
Laskowski, Adrienne
Sourris, Karly C.
Groschner, Lukas N.
Cooper, Mark E.
Thorburn, David R.
Coughlan, Melinda T.
Title Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease
Formatted title
Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease
Journal name Antioxidants and Redox Signaling   Check publisher's open access policy
ISSN 1523-0864
1557-7716
Publication date 2013-08-01
Year available 2013
Sub-type Article (original research)
DOI 10.1089/ars.2012.4719
Open Access Status Not Open Access
Volume 19
Issue 4
Start page 331
End page 343
Total pages 13
Place of publication New Rochelle, NY United States
Publisher Mary Ann Liebert, Inc.
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
 
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Created: Mon, 15 Dec 2014, 21:46:48 EST by Ms Kate Rowe on behalf of Mater Research Institute-UQ