Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status
Anderson, Aidan Alfahad, Nada Wimalachandra, Dulani Bouzinab, Kaouthar Rudzinska, Paula Wood, Heather Fazey, Isabel Xu, Heping Lyons, Timothy J Barnes, Nicholas M
Anderson, Aidan
Alfahad, Nada
Wimalachandra, Dulani
Bouzinab, Kaouthar
Rudzinska, Paula
Wood, Heather
Fazey, Isabel
Xu, Heping
Lyons, Timothy J
Barnes, Nicholas M
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Affiliation
University of Birmingham; Queen's University Belfast; Medical University of South Carolina; Sandwell and West Birmingham NHS Trust; et al.
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Publication date
2024-02-06
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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.
Citation
Anderson A, Alfahad N, Wimalachandra D, Bouzinab K, Rudzinska P, Wood H, Fazey I, Xu H, Lyons TJ, Barnes NM, Narendran P, Lord JM, Rauz S, Ganley IG, Curtis TM, Wallace GR, Hombrebueno JR. Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status. Nat Commun. 2024 Feb 6;15(1):1124. doi: 10.1038/s41467-024-45387-9
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Article