title: Deficiency in mitochondrial complex I activity due to Ndufs6 gene trap insertion induces renal disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: Glycation, Nutrition and Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors: Josephine M
authors: JM
authors: Forbes
authors: Bi-Xia
authors: BX
authors: Ke
authors: Tuong-Vi
authors: TV
authors: Nguyen
authors: Darren C
authors: DC
authors: Henstridge
authors: Sally A
authors: SA
authors: Penfold
authors: Adrienne
authors: A
authors: Laskowski
authors: Karly C
authors: KC
authors: Sourris
authors: Lukas N
authors: LN
authors: Groschner
authors: Mark E
authors: ME
authors: Cooper
authors: David R
authors: DR
authors: Thorburn
authors: Melinda T
authors: MT
authors: Coughlan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I