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

Coughlan, Melinda T., Higgins, Gavin C., Tuong-Vi Nguyen, Penfold, Sally A., Thallas-Bonke, Vicki, Tan, Sih Mm, 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, Ekinci, Elif I., Wijeyeratne, Xiaonan W., Gallo, Linda A., Heiman-Edelstein, Michal, Ryan, Michael T., Cooper, Mark E., Thorburn, David R. and Forbes, Josephine M. (2016) Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis. Diabetes, 65 4: 1085-1098. doi:10.2337/db15-0864


Author Coughlan, Melinda T.
Higgins, Gavin C.
Tuong-Vi Nguyen
Penfold, Sally A.
Thallas-Bonke, Vicki
Tan, Sih Mm
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
Ekinci, Elif I.
Wijeyeratne, Xiaonan W.
Gallo, Linda A.
Heiman-Edelstein, Michal
Ryan, Michael T.
Cooper, Mark E.
Thorburn, David R.
Forbes, Josephine M.
Title Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
1939-327X
Publication date 2016-04
Year available 2016
Sub-type Article (original research)
DOI 10.2337/db15-0864
Open Access Status Not Open Access
Volume 65
Issue 4
Start page 1085
End page 1098
Total pages 14
Place of publication Alexandria, VA United States
Publisher American Diabetes Association
Collection year 2017
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
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