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

Josephine M Forbes, Bi-Xia Ke, Tuong Vi Nguyen, Darren C Henstridge, Sally A Penfold, Adrienne Laskowski, Karly Sourris, Lukas N Groschner, Mark Cooper, David R Thorburn, Melinda T Coughlan

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)


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 Ndufs6 gt/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. ? 2013, Mary Ann Liebert, Inc.
Original languageEnglish
Pages (from-to)331-343
Number of pages13
JournalAntioxidants and Redox Signaling
Issue number4
Publication statusPublished - 2013

Cite this