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Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis

Citation

Coughlan, MT and Higgins, GC and Nguyen, T-V and Penfold, SA and Thallas-Bonke, V and Tan, SM and Ramm, G and Van Bergen, NJ and Henstridge, DC and Sourris, KC and Harcourt, BE and Trounce, IA and Robb, PM and Laskowski, A and McGee, SL and Genders, AJ and Walder, K and Drew, BG and Gregorevic, P and Qian, H and Thomas, MC and Jerums, G and Macisaac, RJ and Skene, A and Power, DA and Ekinci, EI and Wijeyeratne, XW and Gallo, LA and Herman-Edelstein, M and Ryan, MT and Cooper, ME and Thorburn, DR and Forbes, JM, Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis, Diabetes, 65, (4) pp. 1085-1098. ISSN 0012-1797 (2016) [Refereed Article]

Copyright Statement

Copyright 2016 by the American Diabetes Association

DOI: doi:10.2337/db15-0864

Abstract

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.

Item Details

Item Type:Refereed Article
Keywords:adenosine triphosphate, albumin, apoptosis inducing factor, collagen type 4, cystatin C, glucose, mitofusin 1, neutrophil gelatinase associated lipocalin, reactive oxygen metabolite, reduced nicotinamide adenine dinucleotide phosphate oxidase 4
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell metabolism
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Henstridge, DC (Mr Darren Henstridge)
ID Code:133359
Year Published:2016
Web of Science® Times Cited:21
Deposited By:Health Sciences
Deposited On:2019-06-24
Last Modified:2019-07-22
Downloads:0

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