Uncoupled turnover disrupts mitochondrial quality control in diabetic retinopathy

Research output: Contribution to journalArticlepeer-review

Authors

  • Lauren Cairns
  • Louise Dutton
  • Timothy Lyons
  • Derek Brazil
  • Paul Moynagh
  • Tim Curtis
  • Heping Xu

Colleges, School and Institutes

Abstract

Mitochondrial quality control (MQC) is crucial for regulating CNS homeostasis, and its disruption has been implicated in the pathogenesis of some of the most common neurodegenerative diseases. In healthy tissues, the maintenance of MQC depends upon an exquisite balance between mitophagy (removal of damaged mitochondria by autophagy) and biogenesis (de novo synthesis of mitochondria). Here, we show that mitophagy is disrupted in diabetic retinopathy (DR) and decoupled from mitochondrial biogenesis during the progression of the disease. Diabetic retinas from human postmortem donors and experimental mice exhibit a net loss of mitochondrial contents during the early stages of the disease process. Using diabetic mitophagy-reporter mice (mitoQC-Ins2Akita) alongside pMitoTimer (a molecular clock to address mitochondrial age dynamics), we demonstrate that mitochondrial loss arose due to an inability of mitochondrial biogenesis to compensate for diabetes-exacerbated mitophagy. However, as diabetes duration increases, Pink1-dependent mitophagy deteriorates, leading to the build-up of mitochondria primed for degradation in DR. Impairment of mitophagy during prolonged diabetes is linked with the development of retinal senescence, a phenotype that blunted hyperglycemia-induced mitophagy in mitoQC primary Müller cells. Our findings suggest that normalizing mitochondrial turnover may preserve MQC and provide therapeutic options for the management of DR-associated complications.

Details

Original languageEnglish
Article numbere129760
JournalJCI Insight
Volume4
Issue number23
Early online date29 Oct 2019
Publication statusPublished - 5 Dec 2019

Keywords

  • Autophagy, Mitochondria, Neuroscience, Ophthalmology, Retinopathy