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

<p><strong>Aims: </strong> 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 <i> per se</i> is associated with development of renal disease, mice with a knockdown of the complex I gene, <i>Ndufs6</i> were studied. </p> <p><strong>Results: </strong> <i>Ndufs6</i> mice had a partial renal cortical complex I deficiency; <i>Ndufs6^gt/gt</i>, 32% activity and <i>Ndufs6^gt</i>^/+, 83% activity compared with wild-type mice. Both <i>Ndufs6^gt</i>^/+ and <i>Ndufs6^gt/gt</i> 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 <i>Ndufs6^gt/gt</i> 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 F_2t, and up-regulation of antioxidant defence. Juvenile <i>Ndufs6^gt/gt</i> mice also exhibited signs of early renal impairment with increased urinary Kim-1 excretion and elevated circulating cystatin C. </p> <p><strong>Innovation: </strong> 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. </p> <p><strong>Conclusion: </strong> These studies identify for the first time that complex I deficiency as the result of interruption of <i>Ndufs6</i> is an independent cause of renal impairment. </p>