Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration
Open accessAbstract
Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity in neurons leading to LD accumulation in glia prior to or at the onset of neurodegeneration. The accumulated lipids are peroxidated in the presence of ROS. Reducing LD accumulation in glia and lipid peroxidation via targeted lipase overexpression and/or lowering ROS significantly delays the onset of neurodegeneration. Furthermore, a similar pathway leads to glial LD accumulation in Ndufs4 mutant mice with neuronal mitochondrial defects, suggesting that LD accumulation following mitochondrial dysfunction is an evolutionarily conserved phenomenon, and represents an early, transient indicator and promoter of neurodegenerative disease.
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Astrocytes store neuron-derived lipids in lipid droplets, which protect against neurotoxicity.
“Other studies demonstrated that lipid peroxides formed in neurons under oxidative or excitotoxic stress can be transported by APOE-lipoproteins to astrocytes; astrocytes store these neuron-derived lipids in LDs, which protect against neurotoxicity and may play a role in detoxifying these deleterious lipid species (Walker et al., 2006; Liu et al., 2015, 2017; Ioannou et al., 2019; Moulton et al., 2”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Liu et al., 2015
The Results sections report lipid droplets accumulating in glia after neuronal mitochondrial defects, but do not establish that astrocytes store lipids transported from neurons. More importantly, the Results report that reducing glial lipid-droplet accumulation delays neurodegeneration—the opposite of the claimed protection against neurotoxicity. The indexed passages have no page numbers. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredOil-red-O positive lipid-laden cells, including neurons, astrocytes, ependymal cells and Iba1+ cells, have been reported in mice and shown to increase with age.
“Oil-red-O positive “lipid-laden” cells, including neurons, astrocytes, ependymal cells and Iba1+ cells have recently been reported in mice and shown to increase with age 14.”
From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [14]
The Results section on Ndufs4−/− mice reports lipid droplets in mouse brain cells bearing astrocyte and microglia markers. It does not report Oil-red-O staining or lipid-laden ependymal cells or neurons. Nor does it show a general increase with age: droplets progressively disappeared in the vestibular nucleus as the mutant mice aged, although they persisted in the olfactory bulb (page unavailable in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measuredMany LDs in iMGs are peroxidated, suggesting that ROS may also occur first and the peroxidized lipids are sequestered in LDs.
“However, many LDs in iMGs were also peroxidated (Extended Data Fig. 11b–e), suggesting that ROS may also occur first and the peroxidized lipids are sequestered in LDs16,42,52.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [42]
The Results sections on increased ROS and lipid peroxidation report that ROS may promote glial lipid-droplet accumulation and that accumulated lipids are peroxidated. They do not establish the proposed sequence in which lipids are peroxidated first and then sequestered in droplets. The observation about iMGs is the citing authors’ own result, not a finding attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn the brain, LDs accumulate in glial cells upon neuronal oxidative stress and during aging.
“In the brain, LDs accumulate in glial cells upon neuronal oxidative stress and during aging (Liu et al., 2015; Marschallinger et al., 2020)”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Liu et al., 2015
The Results sections on neuronal mitochondrial dysfunction and Ndufs4−/− mice support glial lipid-droplet accumulation associated with neuronal oxidative stress. They do not establish that aging itself causes this accumulation: the section on transient glial lipid droplets reports that droplet numbers decreased as the mutant flies aged. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn neuron-glia co-culture, mitochondrial OXPHOS inhibitor rotenone or knockout of Ndufs4 in neurons leads to glial lipid droplet accumulation.
“In neuron-glia co-culture, mitochondrial OXPHOS inhibitor rotenone or the knockout of Ndufs4 in neurons leads to glial LD accumulation (Liu et al., 2015).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Liu et al., 2015
The Results section on Ndufs4−/− mice reports glial lipid droplets in knockout mice and after neuronal Ndufs4 RNAi knockdown in flies (page unavailable). These findings support the link between Ndufs4 disruption and glial lipid droplets, but they are not neuron–glia co-culture experiments or a neuron-specific Ndufs4 knockout. Our copy does not report the claimed rotenone treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Lipid peroxides formed in neurons under oxidative or excitotoxic stress can be transported by APOE-lipoproteins to astrocytes.
“Other studies demonstrated that lipid peroxides formed in neurons under oxidative or excitotoxic stress can be transported by APOE-lipoproteins to astrocytes; astrocytes store these neuron-derived lipids in LDs, which protect against neurotoxicity and may play a role in detoxifying these deleterious lipid species (Walker et al., 2006; Liu et al., 2015, 2017; Ioannou et al., 2019; Moulton et al., 2”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Liu et al., 2015
The Discussion (page not provided) links neuronal mitochondrial defects and elevated ROS to lipid synthesis in neurons and lipid droplets in glia. The Results section on lipid peroxidation (page not provided) reports peroxidated lipids in this setting. Neither passage shows that lipid peroxides form in neurons and are transported to astrocytes by APOE-lipoproteins. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNeurons are vulnerable to toxic lipids, such as oxidized lipids, particularly when lysosomes are compromised.
“neurons are vulnerable to toxic lipids, such as oxidized lipids65,66, particularly when lysosomes are compromised67.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [65]
ROS elevation as a result of neuronal mitochondrial dysfunction and JNK activation drives LDAM formation in flies.
“It was determined that ROS elevation as a result of neuronal mitochondrial dysfunction and JNK activation drives LDAM formation in flies.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [163]
In mouse and fly models of neurodegeneration, LD accumulation correlates with the onset of neuronal death.
“In mouse and fly models of neurodegeneration, LD accumulation correlates with the onset of neuronal death, suggesting a crucial role for LDAM in neuronal loss [163].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [163]
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Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384 · see citing works
Simpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044 · see citing works
“Antioxidant treatment or human superoxide dismutase 1 (SOD1) expression in flies reduces LD formation and attenuates neurodegeneration [163].”
BackgroundNeuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity
Ioannou, M. S., Jackson, J., Sheu, S.-H., Chang, C.-L., Weigel, A. V., Liu, H., Pasolli, H. A., Xu, C. S., Pang, S., Matthies, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.001 · Cited by 760 · see citing works
TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
Nugent, A. A., Lin, K., van Lengerich, B., Lianoglou, S., Przybyla, L., Davis, S. S., Llapashtica, C., Wang, J., Kim, D. J., Xia, D., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.12.007 · Cited by 745 · see citing works
Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk
Efthymiou, A. G., & Goate, A. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0184-x · Cited by 562 · see citing works
Amyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580 · see citing works
Liu, L., MacKenzie, K. R., Putluri, N., Maletić-Savatić, M., & Bellen, H. J. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.024 · Cited by 556 · see citing works
Self-citationMicroglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases
Bartels, T., De Schepper, S., & Hong, S. (2020) · Science · doi:10.1126/science.abb8587 · Cited by 412 · see citing works
ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism
Qi, G., Mi, Y., Shi, X., Gu, H., Brinton, R. D., & Yin, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108572 · Cited by 379 · see citing works
Lipid droplets in the nervous system
Ralhan, I., Chang, C.-L., Lippincott-Schwartz, J., & Ioannou, M. S. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202102136 · Cited by 281 · see citing works
Fernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277 · see citing works
Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
Feringa, F. M., & van der Kant, R. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.690372 · Cited by 226 · see citing works
Lipid Metabolism Crosstalk in the Brain: Glia and Neurons
Barber, C. N., & Raben, D. M. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00212 · Cited by 188 · see citing works
Axonal Degeneration during Aging and Its Functional Role in Neurodegenerative Disorders
Salvadores, N., Sanhueza, M., Manque, P., & Court, F. A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00451 · Cited by 182 · see citing works
Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases
Yang, D., Wang, X., Zhang, L., Fang, Y., Zheng, Q., Liu, X., Yu, W., Chen, S., Ying, J., & Hua, F. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00828-0 · Cited by 179 · see citing works
Apolipoprotein E4 Alters Astrocyte Fatty Acid Metabolism and Lipid Droplet Formation
Farmer, B., Kluemper, J., & Johnson, L. (2019) · Cells · doi:10.3390/cells8020182 · Cited by 164 · see citing works
The cell biology of APOE in the brain
Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103 · see citing works
APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
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Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · see citing works
“Of note, neurons are vulnerable to toxic lipids, such as oxidized lipids, 65,66 particularly when lysosomes are compromised.”
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Liver Soluble Epoxide Hydrolase Regulates Behavioral and Cellular Effects of Chronic Stress
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Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes
Ignatenko, O., Malinen, S., Rybas, S., Vihinen, H., Nikkanen, J., Kononov, A., Jokitalo, E. S., Ince-Dunn, G., & Suomalainen, A. (2023) · Journal of Cell Biology · doi:10.1083/jcb.202203019 · Cited by 63 · see citing works
PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia
Kozlova, A., Zhang, S., Sudwarts, A., Zhang, H., Smirnou, S., Byeon, S. K., Thapa, C., Sun, X., Stephenson, K., Zhao, X., et al. (2025) · Nature · doi:10.1038/s41586-025-09486-x · Cited by 53 · see citing works
“Lipids are often peroxidated in the presence of ROS, mediating cellular oxidative stress 42 .”
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- Authors
- Liu, L., Zhang, K., Sandoval, H., Yamamoto, S., Jaiswal, M., Sanz, E., Li, Z., Hui, J., Graham, B. H., Quintana, A., & Bellen, H. J.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Seattle Children's Research Institute (US)
- University of Washington (US)
- Corresponding author
- Bellen, Hugo J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 160
- Issue
- 1-2
- Pages
- 177-190
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4377295
- OpenAlex
- W2043234667
- Cited by
- 876
- References
- 76
- Citations by year
- 2026: 63 · 2025: 114 · 2024: 119 · 2023: 103 · 2022: 79 · 2021: 87 · 2020: 88 · 2019: 73 · 2018: 56 · 2017: 46 · 2016: 27 · 2015: 19
- FWCI
- 38.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM084947, T32GM008507, K12GM084897, RC4GM096355, R01GM098387, R01GM067858)
- National Institute of Neurological Disorders and Stroke (T32NS043124)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092, P30HD024064)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- reactive oxygen species, mitochondrial dysfunction, neurodegeneration, JNK signaling, SREBP, lipid peroxidation, lipase, NDUFS4, Drosophila, glia
- MeSH terms
- Animals, Mitochondria, Neuroglia, Neurons, Reactive Oxygen Species, Mice, Knockout, Neurodegenerative Diseases, Electron Transport Complex I, MAP Kinase Kinase 4, Mice, Sterol Regulatory Element Binding Proteins, Lipid Droplets
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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