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

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. and Forbes, Josephine M. 2016, Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis, Diabetes, vol. 65, no. 4, pp. 1085-1098, doi: 10.2337/db15-0864.

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Title Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis
Author(s) 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.ORCID iD for McGee, Sean L.
Genders, Amanda J.
Walder, KenORCID iD for 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.
Journal name Diabetes
Volume number 65
Issue number 4
Start page 1085
End page 1098
Total pages 14
Publisher American Diabetes Association
Place of publication Alexandria, Va.
Publication date 2016-04
ISSN 1939-327X
Summary 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.
Language eng
DOI 10.2337/db15-0864
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, American Diabetes Association
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Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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Created: Wed, 27 Jul 2016, 15:48:56 EST

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