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Mitochondrial dysfunction in diabetic kidney disease

Key Points

  • The kidneys are highly metabolic organs, and their function is tightly coupled to mitochondrial energy production

  • Kidneys share their reliance on mitochondrial energy production with other organs that are similarly susceptible to diabetes complications, such as the heart and nervous system

  • Dysfunctional mitochondria are present in nondiabetic kidney disease and in diabetic kidneys; defects include impaired respiratory chain function, structural and networking abnormalities, disrupted cellular signalling and increased reactive oxygen species generation

  • Diabetes alters the delivery of substrates and oxygen to the kidneys and results in switching to alternative substrates for ATP production to meet increased energy requirements, including a shift towards glucose oxidation in the proximal tubules

  • Mitochondrial fission and fusion events enable energy demands to be met and provide mitochondrial quality control; disruption of these events in diabetes prevents elimination of damaged mitochondria and exacerbates ATP deficits

  • Evidence from preclinical models suggests that mitochondrial damage in diabetes can be pharmacologically repaired to improve kidney function; several potential therapies are currently in clinical trials for mitochondriopathies and/or chronic kidney disease

Abstract

Globally, diabetes is the leading cause of chronic kidney disease and end-stage renal disease, which are major risk factors for cardiovascular disease and death. Despite this burden, the factors that precipitate the development and progression of diabetic kidney disease (DKD) remain to be fully elucidated. Mitochondrial dysfunction is associated with kidney disease in nondiabetic contexts, and increasing evidence suggests that dysfunctional renal mitochondria are pathological mediators of DKD. These complex organelles have a broad range of functions, including the generation of ATP. The kidneys are mitochondrially rich, highly metabolic organs that require vast amounts of ATP for their normal function. The delivery of metabolic substrates for ATP production, such as fatty acids and oxygen, is altered by diabetes. Changes in metabolic fuel sources in diabetes to meet ATP demands result in increased oxygen consumption, which contributes to renal hypoxia. Inherited factors including mutations in genes that impact mitochondrial function and/or substrate delivery may also be important risk factors for DKD. Hence, we postulate that the diabetic milieu and inherited factors that underlie abnormalities in mitochondrial function synergistically drive the development and progression of DKD.

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Figure 1: Energy production in renal mitochondria in early diabetic kidney disease.
Figure 2: Gluconeogenesis and glycolysis in proximal tubule cells.
Figure 3: Alterations in renal mitochondrial dynamics in the diabetic kidney.

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Acknowledgements

J.M.F. was supported by fellowships from the National Health and Medical Research Council of Australia (NH&MRC; 10045031 and 102935) and grants from the US National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Diabetes Complications Consortium (25034–61), the NH&MRC (1023664), Kidney Health Australia and the Mater Foundation. D.R.T. was supported by a Principal Research Fellowship and grants from the NH&MRC (1022896, 1068409 and 1107094).

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Supplementary information

Supplementary information S1 (table)

Oxygen delivery and consumption at rest and mitochondrial density by organ. (DOC 36 kb)

Glossary

Arterio-venous shunting

Mixing of oxygenated and deoxygenated blood through channels between the arterial and venous systems that bypass capillary networks.

Intraglomerular capillary sphincters

Narrowings in glomerular capillaries that are encircled with smooth muscle. Dilatation or constriction of these sphincters modulates blood flow.

Tubuloglomerular feedback

An adaptive mechanism that links the rate of glomerular filtration to the concentration of salt in the tubule fluid, which is sensed by specialized cells in the macula densa.

Fanconi syndrome

A rare syndrome in which the proximal tubules of the kidney are unable to reabsorb solutes adequately. Fanconi syndrome may be inherited or caused by severe renal stressors.

Leigh disease

A rare inherited (via either nuclear or mtDNA) neurometabolic syndrome that causes death in the first few years of life and may have renal manifestations.

State III respiration

A high steady state of mitochondrial respiration (OXPHOS) that occurs following the addition of adenosine diphosphate in the presence of OXPHOS substrates.

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Forbes, J., Thorburn, D. Mitochondrial dysfunction in diabetic kidney disease. Nat Rev Nephrol 14, 291–312 (2018). https://doi.org/10.1038/nrneph.2018.9

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