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Cited by 66Mitochondrial Function and PathologyAutophagy in Disease and TherapyNeuroinflammation and Neurodegeneration Mechanisms

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Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy

Open access
Ignatenko, Olesia, Chilov, Dmitri, Paetau, Ilse, de Miguel, Elena, Jackson, Christopher B., Capin, Gabrielle, Paetau, Anders, Terzioglu, Mugen, Euro, Liliya, Suomalainen, Anu·2018·Nature Communications
DOI 10.1038/s41467-017-01859-9PMC PMC5754366
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Abstract

Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying the clinical variability remain poorly understood. To clarify whether different brain cells have differential sensitivity to mitochondrial dysfunction, we induced mitochondrial DNA (mtDNA) depletion in either neurons or astrocytes of mice, by inactivating Twinkle (TwKO), the replicative mtDNA helicase. Here we show that astrocytes, the most abundant cerebral cell type, are chronically activated upon mtDNA loss, leading to early-onset spongiotic degeneration of brain parenchyma, microgliosis and secondary neurodegeneration. Neuronal mtDNA loss does not, however, cause symptoms until 8 months of age. Findings in astrocyte-TwKO mimic neuropathology of Alpers syndrome, infantile-onset mitochondrial spongiotic encephalopathy caused by mtDNA maintenance defects. Our evidence indicates that (1) astrocytes are dependent on mtDNA integrity; (2) mitochondrial metabolism contributes to their activation; (3) chronic astrocyte activation has devastating consequences, underlying spongiotic encephalopathy; and that (4) astrocytes are a potential target for interventions.

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  • Chronic global mtDNA damage in all central nervous system cells in mice causes profound morphological changes in astrocytes.

    “a previous report has shown that chronic global mtDNA damage in all central nervous system cells in mice causes profound morphological changes in astrocytes (Ignatenko et al. 2018).”

    From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Ignatenko et al. 2018

    The Results section, “Loss of mtDNA maintenance activates astrocytes” (page unavailable), reports progressive activation and reactive morphology in astrocytes after mtDNA depletion. But the paper depleted mtDNA in astrocytes or neurons in separate mouse models, not globally in all central nervous system cells; that condition in the citing sentence is unsupported. (LLM, conf=0.89)

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Metadata

Authors
Ignatenko, O., Chilov, D., Paetau, I., de Miguel, E., Jackson, C. B., Capin, G., Paetau, A., Terzioglu, M., Euro, L., & Suomalainen, A.
Affiliations
University of Helsinki (FI)
Corresponding author
Suomalainen, Anu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-01-04
Volume
9
Issue
1
Pages
70-70
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-01859-9
PMC
PMC5754366
OpenAlex
W2776267522
Cited by
66
References
7
Citations by year
2026: 13 · 2025: 6 · 2024: 13 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 3
FWCI
1.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • Helsingin Yliopisto
  • Novartis Foundation
  • Novartis Stiftung für Medizinisch-Biologische Forschung
  • Sigrid Juséliuksen Säätiö
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
mitochondrial DNA depletion, astrocyte activation, Alpers syndrome, Twinkle helicase, mitochondrial dysfunction, microglial activation, secondary neurodegeneration, mitochondrial metabolism
MeSH terms
Animals, Astrocytes, Brain, Brain Diseases, DNA Helicases, DNA, Mitochondrial, Microscopy, Electron, Mutation, Neurons, Mice, Knockout, Mitochondrial Proteins, Mitochondrial Diseases

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