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

Melinda T. Coughlan, Gavin C. Higgins, Tuong-Vi Nguyen, Sally A. Penfold, Vicki Thallas-Bonke, Sih Min Tan, Georg Ramm, Nicole J. Van Bergen, Darren C. Henstridge, Karly C. Sourris, Brooke E. Harcourt, Ian A. Trounce, Portia M. Robb, Adrienne Laskowski, Sean L. McGee, Amanda J. Genders, Ken Walder, Brian G. Drew, Paul Gregorevic, Hongwei Qian & 13 others Merlin C. Thomas, George Jerums, Richard J. Macisaac, Alison Skene, David A. Power, Elif I. Ekinci, Xiaonan W. Wijeyeratne, Linda A. Gallo, Michal Herman-Edelstein, Michael T. Ryan, Mark E. Cooper, David R. Thorburn, Josephine M. Forbes

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1085-1098
Number of pages14
JournalDiabetes
Volume65
Issue number4
DOIs
Publication statusPublished - Apr 2016

Cite this

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. / Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis. In: Diabetes. 2016 ; Vol. 65, No. 4. pp. 1085-1098.
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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.",
author = "Coughlan, {Melinda T.} and Higgins, {Gavin C.} and Tuong-Vi Nguyen and Penfold, {Sally A.} and Vicki Thallas-Bonke and Tan, {Sih Min} and Georg Ramm and {Van Bergen}, {Nicole J.} and Henstridge, {Darren C.} and Sourris, {Karly C.} and Harcourt, {Brooke E.} and Trounce, {Ian A.} and Robb, {Portia M.} and Adrienne Laskowski and McGee, {Sean L.} and Genders, {Amanda J.} and Ken Walder and Drew, {Brian G.} and Paul Gregorevic and Hongwei Qian and Thomas, {Merlin C.} and George Jerums and Macisaac, {Richard J.} and Alison Skene and Power, {David A.} and Ekinci, {Elif I.} and Wijeyeratne, {Xiaonan W.} and Gallo, {Linda A.} and Michal Herman-Edelstein and Ryan, {Michael T.} and Cooper, {Mark E.} and Thorburn, {David R.} and Forbes, {Josephine M.}",
year = "2016",
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doi = "10.2337/db15-0864",
language = "English",
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Coughlan, MT, Higgins, GC, Nguyen, T-V, Penfold, SA, Thallas-Bonke, V, Tan, SM, Ramm, G, Van Bergen, NJ, Henstridge, DC, Sourris, KC, Harcourt, BE, Trounce, IA, Robb, PM, Laskowski, A, McGee, SL, Genders, AJ, Walder, K, Drew, BG, Gregorevic, P, Qian, H, Thomas, MC, Jerums, G, Macisaac, RJ, Skene, A, Power, DA, Ekinci, EI, Wijeyeratne, XW, Gallo, LA, Herman-Edelstein, M, Ryan, MT, Cooper, ME, Thorburn, DR & Forbes, JM 2016, 'Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis' Diabetes, vol. 65, no. 4, pp. 1085-1098. https://doi.org/10.2337/db15-0864

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.; Forbes, Josephine M.

In: Diabetes, Vol. 65, No. 4, 04.2016, p. 1085-1098.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Deficiency in apoptosis-inducing factor recapitulates chronic kidney disease via aberrant mitochondrial homeostasis

AU - Coughlan, Melinda T.

AU - Higgins, Gavin C.

AU - Nguyen, Tuong-Vi

AU - Penfold, Sally A.

AU - Thallas-Bonke, Vicki

AU - Tan, Sih Min

AU - Ramm, Georg

AU - Van Bergen, Nicole J.

AU - Henstridge, Darren C.

AU - Sourris, Karly C.

AU - Harcourt, Brooke E.

AU - Trounce, Ian A.

AU - Robb, Portia M.

AU - Laskowski, Adrienne

AU - McGee, Sean L.

AU - Genders, Amanda J.

AU - Walder, Ken

AU - Drew, Brian G.

AU - Gregorevic, Paul

AU - Qian, Hongwei

AU - Thomas, Merlin C.

AU - Jerums, George

AU - Macisaac, Richard J.

AU - Skene, Alison

AU - Power, David A.

AU - Ekinci, Elif I.

AU - Wijeyeratne, Xiaonan W.

AU - Gallo, Linda A.

AU - Herman-Edelstein, Michal

AU - Ryan, Michael T.

AU - Cooper, Mark E.

AU - Thorburn, David R.

AU - Forbes, Josephine M.

PY - 2016/4

Y1 - 2016/4

N2 - 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.

AB - 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.

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U2 - 10.2337/db15-0864

DO - 10.2337/db15-0864

M3 - Article

VL - 65

SP - 1085

EP - 1098

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -