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Cited by 343Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsMitochondrial Function and Pathology

Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration

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Mi, Yashi, Qi, Guoyuan, Vitali, Francesca, Shang, Yuan, Raikes, Adam C., Wang, Tian, Jin, Yan, Brinton, Roberta D. +2 more·2023·Nature Metabolism
DOI 10.1038/s42255-023-00756-4PMC PMC10202034
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Abstract

Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low mitochondrial oxidative phosphorylation (OxPhos) activity, but its pathophysiological role in neurodegeneration remains unclear. Here, we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of Alzheimer's disease (AD), including synaptic loss, neuroinflammation, demyelination and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Along with LD accumulation and impaired FA degradation manifested in an AD mouse model, we reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.

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  • Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of Alzheimer's disease.

    “Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of AD [16, 17, 18].”

    From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [17]

    The Abstract reports that impaired astrocytic mitochondrial oxidative phosphorylation induces lipid-droplet accumulation followed by AD-like neurodegeneration. But the Discussion describes lipid-droplet formation as a protective response rather than a driver of reactivity or neuroinflammation. The paper therefore does not support the claim that the droplets themselves exacerbate AD progression. (LLM, conf=0.89)

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Cited by

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Authors
Mi, Y., Qi, G., Vitali, F., Shang, Y., Raikes, A. C., Wang, T., Jin, Y., Brinton, R. D., Gu, H., & Yin, F.
Affiliations
  • University of Arizona (US)
  • Florida International University (US)
Corresponding author
Yin, Fei
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2023-03-23
Volume
5
Issue
3
Pages
445-465
ISSN
2522-5812 (ISSN-L)
DOI
10.1038/s42255-023-00756-4
PMC
PMC10202034
OpenAlex
W4360609956
Cited by
343
References
21
Citations by year
2026: 112 · 2025: 141 · 2024: 68 · 2023: 22
FWCI
33.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21AG072561, RF1AG068175, P01AG026572)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
astrocytes, mitochondrial oxidative phosphorylation, fatty acid degradation, lipid homeostasis, lipid droplets, neuroinflammation, neurodegeneration, Alzheimer's disease, astrocyte activation, STAT3 acetylation, acetyl-CoA, microglial activation, myelin maintenance, phospholipid synthesis, oxidative stress, synaptic loss, demyelination
MeSH terms
Neuroinflammatory Diseases, Alzheimer Disease, Animals, Astrocytes, Fatty Acids, Mitochondria, Mice

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