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Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer’s disease models

Yu, Yizhou, Chen, Civia Z., Celardo, Ivana, Tan, Bryan Wei Zhi, Hurcomb, James D., Leal, Nuno Santos, Popovic, Rebeka, Loh, Samantha H. Y., Martins, L. Miguel·2024·Cell Death & Disease
DOI 10.1038/s41419-024-07179-3
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Abstract

Alzheimer’s disease (AD) is the most common form of age-related dementia. In AD, the death of neurons in the central nervous system is associated with the accumulation of toxic amyloid β peptide (Aβ) and mitochondrial dysfunction. Mitochondria are signal transducers of metabolic and biochemical information, and their impairment can compromise cellular function. Mitochondria compartmentalise several pathways, including folate-dependent one-carbon (1C) metabolism and electron transport by respiratory complexes. Mitochondrial 1C metabolism is linked to electron transport through complex I of the respiratory chain. Here, we analysed the proteomic changes in a fly model of AD by overexpressing a toxic form of Aβ (Aβ-Arc). We found that expressing Aβ-Arc caused alterations in components of both complex I and mitochondrial 1C metabolism. Genetically enhancing mitochondrial 1C metabolism through Nmdmc improved mitochondrial function and was neuroprotective in fly models of AD. We also found that exogenous supplementation with the 1C donor folinic acid improved mitochondrial health in both mammalian cells and fly models of AD. We found that genetic variations in MTHFD2L, the human orthologue of Nmdmc, were linked to AD risk. Additionally, Mendelian randomisation showed that increased folate intake decreased the risk of developing AD. Overall, our data suggest enhancement of folate-dependent 1C metabolism as a viable strategy to delay the progression and attenuate the severity of AD.

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Cited by

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Metadata

Authors
Yu, Y., Chen, C. Z., Celardo, I., Tan, B. W. Z., Hurcomb, J. D., Leal, N. S., Popovic, R., Loh, S. H. Y., & Martins, L. M.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2024-11-24
Volume
15
Issue
11
ISSN
2041-4889
DOI
10.1038/s41419-024-07179-3
Cited by
10
References
13
Language
en
Licence
Funders
RCUK | Medical Research Council (RG94521)

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