Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy?
Diabetic nephropathy (DN) is a progressive microvascular complication arising from diabetes. Within the kidney, the glomeruli, tubules, vessels and interstitium are disrupted, ultimately impairing renal function and leading to end-stage renal disease (ESRD). Current pharmacological therapies used in individuals with DN do not prevent the inevitable progression to ESRD; therefore, new targets of therapy are urgently required. Studies from animal models indicate that disturbances in mitochondrial homeostasis are central to the pathogenesis of DN. Since renal proximal tubule cells rely on oxidative phosphorylation to provide adequate ATP for tubular reabsorption, an impairment of mitochondrial bioenergetics can result in renal functional decline. Defects at the level of the electron transport chain have long been established in DN, promoting electron leakage and formation of superoxide radicals, mediating microinflammation and contributing to the renal lesion. More recent studies suggest that mitochondrial-associated proteins may be directly involved in the pathogenesis of tubulointerstitial fibrosis and glomerulosclerosis. An accumulation of fragmented mitochondria are found in the renal cortex in both humans and animals with DN, suggesting that in tandem with a shift in dynamics, mitochondrial clearance mechanisms may be impaired. The process of mitophagy is the selective targeting of damaged or dysfunctional mitochondria to autophagosomes for degradation through the autophagy pathway. The current review explores the concept that an impairment in the mitophagy system leads to the accelerated progression of renal pathology. A better understanding of the cellular and molecular events that govern mitophagy and dynamics in DN may lead to improved therapeutic strategies.
Glycation, Nutrition & Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
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Higgins
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Coughlan
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D005355:Fibrosis / Q000503:physiopathology; D006801:Humans; D028361:Mitochondrial Diseases / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D063306:Mitophagy / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D058990:Molecular Targeted Therapy
D000975:Antioxidants
autophagy; diabetes; diabetic nephropathy; dynamics; kidney; mitochondria; mitochondrial dysfunction; mitophagy