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, Timothy J. Lyons, Nicholas M. Barnes, Parth Narendran, Janet M. Lord, Saaeha Rauz, Ian G. Ganley, Tim M. Curtis, Graham R. Wallace and Jose R. Hombrebueno ()
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Aidan Anderson: University of Birmingham
Nada Alfahad: University of Birmingham
Dulani Wimalachandra: University of Birmingham
Kaouthar Bouzinab: University of Birmingham
Paula Rudzinska: University of Birmingham
Heather Wood: University of Birmingham
Isabel Fazey: University of Birmingham
Heping Xu: Queen’s University Belfast
Timothy J. Lyons: Medical University of South Carolina
Nicholas M. Barnes: University of Birmingham
Parth Narendran: University of Birmingham
Janet M. Lord: University of Birmingham
Saaeha Rauz: University of Birmingham
Ian G. Ganley: University of Dundee
Tim M. Curtis: Queen’s University Belfast
Graham R. Wallace: University of Birmingham
Jose R. Hombrebueno: University of Birmingham

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45387-9

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