title: Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis.
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.
authors.affiliation: 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.
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Higgins
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Tuong-Vi
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Penfold
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas-Bonke
authors.affiliation: 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.
authors.forename: Sih Min
authors.initials: SM
authors.lastname: Tan
authors.affiliation: Membrane Biology Group, Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Victoria, Australia.
authors.forename: Georg
authors.initials: G
authors.lastname: Ramm
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Van Bergen
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.affiliation: 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.
authors.forename: Karly C
authors.initials: KC
authors.lastname: Sourris
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Harcourt
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Trounce
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Portia M
authors.initials: PM
authors.lastname: Robb
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Laskowski
authors.affiliation: Metabolic Research Unit, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Metabolic Research Unit, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Genders
authors.affiliation: Metabolic Research Unit, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.affiliation: Endocrine Centre, Austin Health, Repatriation Campus, Heidelberg West, Victoria, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Jerums
authors.affiliation: Departments of Endocrinology and Diabetes, St Vincent's Hospital Melbourne and The University of Melbourne, Fitzroy, Victoria, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Macisaac
authors.affiliation: Department of Anatomical Pathology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Alison
authors.initials: A
authors.lastname: Skene
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Power
authors.affiliation: 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.
authors.forename: Elif I
authors.initials: EI
authors.lastname: Ekinci
authors.affiliation: Department of Biochemistry, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Xiaonan W
authors.initials: XW
authors.lastname: Wijeyeratne
authors.affiliation: Glycation and Diabetes Group, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, South Brisbane, Queensland, Australia.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Gallo
authors.affiliation: The Felsenstein Medical Research Center and Department of Nephrology and Hypertension, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Herman-Edelstein
authors.affiliation: Mitochondria Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.affiliation: 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.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: 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.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics*; D019069:Cell Respiration / Q000235:genetics; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: D051033:Apoptosis Inducing Factor; C494830:AIFM1 protein, mouse