Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status

Aidan Anderson, Nada Alfahad, Dulani Wimalachandra, Kaouthar Bouzinab, Paula Rudzinska, Heather Wood, Isabel Fazey, Heping Xu, Nicholas M Barnes, Parth Narendran, Janet M Lord, Saaeha Rauz, Ian G Ganley, Tim M Curtis, Graham R Wallace, Jose R Hombrebueno*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
28 Downloads (Pure)

Abstract

The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.

Original languageEnglish
Article number1124
Number of pages16
JournalNature Communications
Volume15
DOIs
Publication statusPublished - 06 Feb 2024

Bibliographical note

© 2024. The Author(s).

Keywords

  • Male
  • Mice
  • Humans
  • Animals
  • Mitochondrial Dynamics
  • Neuroprotection
  • Diabetes Mellitus, Experimental/metabolism
  • Retina/metabolism
  • Mitochondria/metabolism
  • Adenosine
  • Kinetin

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