University of Tasmania
Browse

File(s) under permanent embargo

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

journal contribution
posted on 2023-05-20, 04:43 authored by Forbes, JM, Ke, B-X, Nguyen, T-V, Darren HenstridgeDarren Henstridge, Penfold, SA, Laskowski, A, Sourris, KC, Groschner, LN, Cooper, ME, Thorburn, DR, Coughlan, MT

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.

History

Publication title

Antioxidants and Redox Signaling

Volume

19

Issue

4

Pagination

331-343

ISSN

1523-0864

Department/School

School of Health Sciences

Publisher

Mary Ann Liebert Inc Publ

Place of publication

2 Madison Avenue, Larchmont, USA, Ny, 10538

Rights statement

Copyright 2013 Mary Ann Liebert, Inc.

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified; Clinical health not elsewhere classified