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Jose Manuel Romero del Hombre, Lauren Cairns, Timothy J Lyons, Paul Moynagh, Tim M Curtis, Heping Xu; Mitochondrial quality control is dysregulated in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6430. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The accumulation of dysfunctional mitochondria is believed to play a pivotal role in the pathogenesis of diabetic retinopathy (DR). In healthy tissues, mitochondrial quality control (MQC) ensures that dysfunctional mitochondria are eliminated (mitophagy) and replaced by newly-synthetized functional units (mitochondrial biogenesis). The aim of this study was to investigate how MQC mechanisms are affected in the retina during the progression of diabetes.
Mitochondrial contents (Cox4) and major adaptors of mitophagy (Pink1), autophagy (Lc3b, p62) and biogenesis (PGC-1α, TFAM) were examined by immunohistochemistry in human and Ins2Akita murine retinas at different stages of diabetes. To address mitophagy unambiguously in vivo, we generated novel diabetic mitophagy-reporter mice (mitoQC-Ins2Akita). The dysregulation of MQC was further evaluated in retinal Müller cells (primary and MIO-M1 cell-line) maintained under elevated glucose concentrations (30.5 mM) for 5 days, by western blot analysis of mitophagy/biogenesis adaptors alongside transfection of pMitoTimer (a novel molecular clock for monitoring the relative age of mitochondria).
Mitochondrial contents were significantly diminished at the early stages of diabetes, as shown in diabetic patients with no clinical signs of retinopathy and Ins2Akita mice after 2-months of hyperglycaemia. Using Ins2Akita mitophagy-reporter mice and pMitoTimer in cultured Müller cells, we showed that mitochondrial loss arose due to an inability of mitochondrial biogenesis to compensate for diabetes-induced mitophagy. Interestingly, mitochondria content increased during the progression of diabetes, as observed in diabetic patients with retinopathy and in Ins2Akita mice after 8-months of diabetes. This shift was not due to increased mitochondrial biogenesis (since its machinery remained depressed), but rather to impaired mitophagy. We also showed that diabetes-induced impairment of mitophagy was associated with cellular senescence, an exclusive phenotype of diabetic retinas during advanced stages of the disease.
Our data suggest that mitochondrial biogenesis is decoupled from mitophagy at the early stages of diabetes, and that mitophagy is compromised during the progression of DR. Since MQC is crucial for central nervous system homeostasis, its normalisation may represent an attractive therapeutic target for the management of DR.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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