Journal article
Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis
Diabetes, Vol.65(4), pp.1085-1098
2016
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.
Details
- Title
- Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis
- Authors
- Melinda T Coughlan (Corresponding Author) - Monash UniversityGavin C Higgins (Author) - Baker Heart and Diabetes InstituteTuong-Vi Nguyen (Author) - Baker Heart and Diabetes InstituteSally A Penfold (Author) - Baker Heart and Diabetes InstituteVicki Thallas-Bonke (Author) - Baker Heart and Diabetes InstituteSih Min Tan (Author) - Baker Heart and Diabetes InstituteGeorg Ramm (Author) - Monash UniversityN J Van Bergen (Author) - The Royal Victorian Eye & Ear HospitalD C Henstridge (Author) - Baker Heart and Diabetes InstituteK C Sourris (Author) - Monash UniversityBrooke E Harcourt (Author) - Murdoch Children's Research InstituteIan A Trounce (Author) - The Royal Victorian Eye & Ear HospitalPortia M Robb (Author) - Baker Heart and Diabetes InstituteAdrienne Laskowski (Author) - Royal Children's HospitalSean McGee (Author) - Deakin UniversityAmanda J Genders (Author) - Deakin UniversityKen Walder (Author) - Deakin UniversityBrian G Drew (Author) - Baker Heart and Diabetes InstitutePaul Gregorevic (Author) - Baker Heart and Diabetes InstituteMerlin C Thomas (Author) - Baker Heart and Diabetes InstituteHongwei Qian (Author) - Baker Heart and Diabetes InstituteJerums George (Author) - Austin HealthRichard J MacIsaac (Author) - University of MelbourneAlison Skene (Author)David Power (Author) - Austin HealthElif Ekinci (Author) - Austin HealthXiaonan W Wijeyeratne (Author) - La Trobe UniversityLinda Gallo (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - LegacySee article text for complete list of authors. (Author)
- Publication details
- Diabetes, Vol.65(4), pp.1085-1098
- Publisher
- American Diabetes Association
- DOI
- 10.2337/db15-0864
- ISSN
- 1939-327X
- Organisation Unit
- University of the Sunshine Coast, Queensland; School of Health and Behavioural Sciences - Legacy; School of Health - Biomedicine
- Language
- English
- Record Identifier
- 99621941002621
- Output Type
- Journal article
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- Endocrinology & Metabolism
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