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 (Lead / Corresponding author)

MRC PPU

Research output: Contribution to journal › Article › peer-review

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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.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-024-45387-9Licence: CC BY

Final published versionFinal published version, 4.1 MBLicence: CC BY

Cite this

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, 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.",

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

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 = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = feb,

day = "6",

doi = "10.1038/s41467-024-45387-9",

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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, 1124. https://doi.org/10.1038/s41467-024-45387-9

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T1 - Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status

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.

PY - 2024/2/6

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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.

KW - Male

KW - Mice

KW - Humans

KW - Animals

KW - Mitochondrial Dynamics

KW - Neuroprotection

KW - Diabetes Mellitus, Experimental/metabolism

KW - Retina/metabolism

KW - Mitochondria/metabolism

KW - Adenosine

KW - Kinetin

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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

M1 - 1124

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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