Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes

Melinda T. Coughlan, Tuong Vi Nguyen, Sally A. Penfold, Gavin C. Higgins, Vicki Thallas-Bonke, Sih Min Tan, Nicole J. Van Bergen, Karly C. Sourris, Brooke E. Harcourt, David R. Thorburn, Ian A. Trounce, Mark E. Cooper, Josephine M. Forbes

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Oxidative phosphorylation (OXPHOS) drives ATP production by mitochondria, which are dynamic organelles, constantly fusing and dividing to maintain kidney homoeostasis. In diabetic kidney disease (DKD), mitochondria appear dysfunctional, but the temporal development of diabetes-induced adaptations in mitochondrial structure and bioenergetics have not been previously documented. In the present study, we map the changes in mitochondrial dynamics and function in rat kidney mitochondria at 4, 8, 16 and 32 weeks of diabetes. Our data reveal that changes in mitochondrial bioenergetics and dynamics precede the development of albuminuria and renal histological changes. Specifically, in early diabetes (4 weeks), a decrease in ATP content and mitochondrial fragmentation within proximal tubule epithelial cells (PTECs) of diabetic kidneys were clearly apparent, but no changes in urinary albumin excretion or glomerular morphology were evident at this time. By 8 weeks of diabetes, there was increased capacity for mitochondrial permeability transition (mPT) by pore opening, which persisted over time and correlated with mitochondrial hydrogen peroxide (H2O2) generation and glomerular damage. Late in diabetes, by week 16, tubular damage was evident with increased urinary kidney injury molecule-1 (KIM-1) excretion, where an increase in the Complex I-linked oxygen consumption rate (OCR), in the context of a decrease in kidney ATP, indicated mitochondrial uncoupling. Taken together, these data show that changes in mitochondrial bioenergetics and dynamics may precede the development of the renal lesion in diabetes, and this supports the hypothesis that mitochondrial dysfunction is a primary cause of DKD.

Original languageEnglish
Pages (from-to)711-720
Number of pages10
JournalClinical Science
Volume130
Issue number9
DOIs
Publication statusPublished - 1 May 2016

Keywords

  • Diabetic nephropathy
  • Experimental diabetes
  • Kidney disease
  • Mitochondria

Cite this

Coughlan, M. T., Nguyen, T. V., Penfold, S. A., Higgins, G. C., Thallas-Bonke, V., Tan, S. M., ... Forbes, J. M. (2016). Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. Clinical Science, 130(9), 711-720. https://doi.org/10.1042/CS20150838
Coughlan, Melinda T. ; Nguyen, Tuong Vi ; Penfold, Sally A. ; Higgins, Gavin C. ; Thallas-Bonke, Vicki ; Tan, Sih Min ; Van Bergen, Nicole J. ; Sourris, Karly C. ; Harcourt, Brooke E. ; Thorburn, David R. ; Trounce, Ian A. ; Cooper, Mark E. ; Forbes, Josephine M. / Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. In: Clinical Science. 2016 ; Vol. 130, No. 9. pp. 711-720.
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abstract = "Oxidative phosphorylation (OXPHOS) drives ATP production by mitochondria, which are dynamic organelles, constantly fusing and dividing to maintain kidney homoeostasis. In diabetic kidney disease (DKD), mitochondria appear dysfunctional, but the temporal development of diabetes-induced adaptations in mitochondrial structure and bioenergetics have not been previously documented. In the present study, we map the changes in mitochondrial dynamics and function in rat kidney mitochondria at 4, 8, 16 and 32 weeks of diabetes. Our data reveal that changes in mitochondrial bioenergetics and dynamics precede the development of albuminuria and renal histological changes. Specifically, in early diabetes (4 weeks), a decrease in ATP content and mitochondrial fragmentation within proximal tubule epithelial cells (PTECs) of diabetic kidneys were clearly apparent, but no changes in urinary albumin excretion or glomerular morphology were evident at this time. By 8 weeks of diabetes, there was increased capacity for mitochondrial permeability transition (mPT) by pore opening, which persisted over time and correlated with mitochondrial hydrogen peroxide (H2O2) generation and glomerular damage. Late in diabetes, by week 16, tubular damage was evident with increased urinary kidney injury molecule-1 (KIM-1) excretion, where an increase in the Complex I-linked oxygen consumption rate (OCR), in the context of a decrease in kidney ATP, indicated mitochondrial uncoupling. Taken together, these data show that changes in mitochondrial bioenergetics and dynamics may precede the development of the renal lesion in diabetes, and this supports the hypothesis that mitochondrial dysfunction is a primary cause of DKD.",
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Coughlan, MT, Nguyen, TV, Penfold, SA, Higgins, GC, Thallas-Bonke, V, Tan, SM, Van Bergen, NJ, Sourris, KC, Harcourt, BE, Thorburn, DR, Trounce, IA, Cooper, ME & Forbes, JM 2016, 'Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes' Clinical Science, vol. 130, no. 9, pp. 711-720. https://doi.org/10.1042/CS20150838

Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. / Coughlan, Melinda T.; Nguyen, Tuong Vi; Penfold, Sally A.; Higgins, Gavin C.; Thallas-Bonke, Vicki; Tan, Sih Min; Van Bergen, Nicole J.; Sourris, Karly C.; Harcourt, Brooke E.; Thorburn, David R.; Trounce, Ian A.; Cooper, Mark E.; Forbes, Josephine M.

In: Clinical Science, Vol. 130, No. 9, 01.05.2016, p. 711-720.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Nguyen, Tuong Vi

AU - Penfold, Sally A.

AU - Higgins, Gavin C.

AU - Thallas-Bonke, Vicki

AU - Tan, Sih Min

AU - Van Bergen, Nicole J.

AU - Sourris, Karly C.

AU - Harcourt, Brooke E.

AU - Thorburn, David R.

AU - Trounce, Ian A.

AU - Cooper, Mark E.

AU - Forbes, Josephine M.

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