Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/19243
Title: Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis.
Authors: Coughlan, Melinda T;Higgins, Gavin C;Nguyen, Tuong-Vi;Penfold, Sally A;Thallas-Bonke, Vicki;Tan, Sih Min;Ramm, Georg;Van Bergen, Nicole J;Henstridge, Darren C;Sourris, Karly C;Harcourt, Brooke E;Trounce, Ian A;Robb, Portia M;Laskowski, Adrienne;McGee, Sean L;Genders, Amanda J;Walder, Ken;Drew, Brian G;Gregorevic, Paul;Qian, Hongwei;Thomas, Merlin C;Jerums, George;Macisaac, Richard J;Skene, Alison;Power, David A;Ekinci, Elif I;Wijeyeratne, Xiaonan W;Gallo, Linda A;Herman-Edelstein, Michal;Ryan, Michael T;Cooper, Mark E;Thorburn, David R;Forbes, Josephine M
Affiliation: Menzies School of Health Research, Darwin, Northern Territory, Australia
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
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
Department of Nephrology, Austin Health, Heidelberg, Victoria, Australia
Institute for Breathing and Sleep, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Glycation and Diabetes Group, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, South Brisbane, Queensland, Australia
The Felsenstein Medical Research Center and Department of Nephrology and Hypertension, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Mitochondria Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
Membrane Biology Group, Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Victoria, Australia
Department of Medicine, Central Clinical School, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
Metabolic Research Unit, Deakin University, Waurn Ponds, Victoria, Australia
Endocrine Centre, Heidelberg Repatriation Hospital, Austin Health, Heidelberg West, Victoria, Australia
Departments of Endocrinology and Diabetes, St Vincent's Hospital Melbourne and The University of Melbourne, Fitzroy, Victoria, Australia
Department of Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia
Department of Biochemistry, La Trobe University, Melbourne, Victoria, Australia
Issue Date: Apr-2016
EDate: 2016-01-28
Citation: Diabetes 2016; 65(4): 1085-1098
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/19243
DOI: 10.2337/db15-0864
ORCID: 0000-0003-2372-395X
PubMed URL: 26822084
Type: Journal Article
Research Support, Non-U.S. Gov't
Appears in Collections:Journal articles

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