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; Jose R. Hombrebueno

doi:10.1038/s41467-024-45387-9

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, Jose R. Hombrebueno^*

^*Corresponding author for this work

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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 (Ins2^Akita 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 language	English
Article number	1124
Number of pages	16
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-45387-9
Publication status	Published - 6 Feb 2024

Bibliographical note

Acknowledgments:
This work was supported by Diabetes UK (20/0006296) to JRH, EFSD/Boehringer Ingelheim Grant to JRH, Fight for Sight (1842/1843) to JRH, Wellcome Trust (213458/Z/18/Z) to JRH and Medical Research Council, UK (MC_UU_00018/2) to IGG. Special thanks to Professor Astrid Limb (University College London) for providing the MIO-M1 cell line. Cartoon in Fig. 3a was created with BioRender.com. We thank the eye donors for their inestimable contribution to diabetes research.

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10.1038/s41467-024-45387-9Licence: Creative Commons: Attribution (CC BY)

AndersonA2024RelaxationFinal published version, 4.1 MBLicence: Creative Commons: Attribution (CC BY)

Rescuing mitochondrial self-repair for the management of diabetic retinopathy
Wallace, G., Romero, J., Rauz, S. & Barnes, N.
Diabetes Uk
10/01/22 → 9/01/25
Project: Research

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Anderson, A., Alfahad, N., Wimalachandra, D., Bouzinab, K., Rudzinska, P., Wood, H., Fazey, I., Xu, H., Lyons, T. J., Barnes, N. M., Narendran, P., Lord, J. M., Rauz, S., Ganley, I. G., Curtis, T. M., Wallace, G. R., & Hombrebueno, J. R. (2024). Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status. Nature Communications, 15(1), Article 1124. https://doi.org/10.1038/s41467-024-45387-9

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

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.",

author = "Aidan Anderson and Nada Alfahad and Dulani Wimalachandra and Kaouthar Bouzinab and Paula Rudzinska and Heather Wood and Isabel Fazey and Heping Xu and Lyons, {Timothy J.} and Barnes, {Nicholas M.} and Parth Narendran and Lord, {Janet M.} and Saaeha Rauz and Ganley, {Ian G.} and Curtis, {Tim M.} and Wallace, {Graham R.} and Hombrebueno, {Jose R.}",

note = "Acknowledgments: This work was supported by Diabetes UK (20/0006296) to JRH, EFSD/Boehringer Ingelheim Grant to JRH, Fight for Sight (1842/1843) to JRH, Wellcome Trust (213458/Z/18/Z) to JRH and Medical Research Council, UK (MC_UU_00018/2) to IGG. Special thanks to Professor Astrid Limb (University College London) for providing the MIO-M1 cell line. Cartoon in Fig. 3a was created with BioRender.com. We thank the eye donors for their inestimable contribution to diabetes research.",

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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 2024, 'Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status', Nature Communications, vol. 15, no. 1, 1124. https://doi.org/10.1038/s41467-024-45387-9

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AU - Anderson, Aidan

AU - Alfahad, Nada

AU - Wimalachandra, Dulani

AU - Bouzinab, Kaouthar

AU - Rudzinska, Paula

AU - Wood, Heather

AU - Fazey, Isabel

AU - Xu, Heping

AU - Lyons, Timothy J.

AU - Barnes, Nicholas M.

AU - Narendran, Parth

AU - Lord, Janet M.

AU - Rauz, Saaeha

AU - Ganley, Ian G.

AU - Curtis, Tim M.

AU - Wallace, Graham R.

AU - Hombrebueno, Jose R.

N1 - Acknowledgments: This work was supported by Diabetes UK (20/0006296) to JRH, EFSD/Boehringer Ingelheim Grant to JRH, Fight for Sight (1842/1843) to JRH, Wellcome Trust (213458/Z/18/Z) to JRH and Medical Research Council, UK (MC_UU_00018/2) to IGG. Special thanks to Professor Astrid Limb (University College London) for providing the MIO-M1 cell line. Cartoon in Fig. 3a was created with BioRender.com. We thank the eye donors for their inestimable contribution to diabetes research.

PY - 2024/2/6

Y1 - 2024/2/6

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-024-45387-9

M3 - Article

C2 - 38321058

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1124

ER -

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

Abstract

Bibliographical note

UN SDGs

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Rescuing mitochondrial self-repair for the management of diabetic retinopathy

Cite this