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Diabetes. 2016 Apr;65(4):1085-98. doi: 10.2337/db15-0864. Epub 2016 Jan 28.

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis.

Author information

1
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia Department of Epidemiology and Preventive Medicine, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia melinda.coughlan@bakeridi.edu.au.
2
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
3
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
4
Membrane Biology Group, Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Victoria, Australia.
5
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
6
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
7
Metabolic Research Unit, Deakin University, Waurn Ponds, Victoria, Australia.
8
Endocrine Centre, Austin Health, Repatriation Campus, Heidelberg West, Victoria, Australia.
9
Departments of Endocrinology and Diabetes, St Vincent's Hospital Melbourne and The University of Melbourne, Fitzroy, Victoria, Australia.
10
Department of Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia.
11
Department of Nephrology and Institute for Breathing and Sleep, Austin Health, Heidelberg, Victoria, Australia Department of Medicine, Austin Health and The University of Melbourne, Parkville, Victoria, Australia.
12
Endocrine Centre, Austin Health, Repatriation Campus, Heidelberg West, Victoria, Australia Department of Medicine, Austin Health and The University of Melbourne, Parkville, Victoria, Australia Menzies School of Health Research, Darwin, Northern Territory, Australia.
13
Department of Biochemistry, La Trobe University, Melbourne, Victoria, Australia.
14
Glycation and Diabetes Group, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, South Brisbane, Queensland, Australia.
15
The Felsenstein Medical Research Center and Department of Nephrology and Hypertension, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
16
Mitochondria Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
17
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia Glycation and Diabetes Group, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, South Brisbane, Queensland, Australia School of Medicine, Mater Clinical School, The University of Queensland, St. Lucia, Queensland, Australia.

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.

PMID:
26822084
DOI:
10.2337/db15-0864
[Indexed for MEDLINE]
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