Streptozotocin-induced astrocyte mitochondrial dysfunction is ameliorated by FTO inhibitor MO-I-500
Abstract
The pathogenesis of Alzheimer's disease (AD), the most prevalent form of dementia, remains unclear. Over the past few years, evidence has accumulated indicating that perturbed cerebral bioenergetics and neuroinflammation may compromise cognitive functions and precedes the onset of AD and that impaired function of glial cells can likely contribute to the development of the disease. Recently, N6-methyladenosine (m6A) modification of RNA has been implicated in the regulation of different processes in the brain and to play a potential role in neurodegeneration. In the present study, we investigated the potential role of the m6A machinery enzymes in a streptozotocin (STZ) model of AD in human astrocytoma CCF-STTG1 cells. We observed that STZ-treated astrocytes expressed significantly higher levels of m6A demethylase fat mass and obesity-associated protein (FTO) and m6A reader YTHDF1 (YTH domain-containing family protein 1). Our experiments revealed that MO-I-500, a novel pharmacological inhibitor of FTO, can strongly reduce the adverse effects of STZ. Inhibition of FTO enhanced the survival of cells exposed to STZ and suppressed oxidative stress, apoptosis, elevated expression of glial fibrillary acidic protein, mitochondrial dysfunction, and bioenergetic disturbances induced by this compound. Overall, the results of this study indicate that perturbed m6A signaling may be contributing to AD pathogenesis, likely by compromising astrocyte bioenergetics.
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m6A regulates inflammation, macrophages and also astrocytosis.
“Such results are consistent with emerging studies showing that m6A regulates inflammation, macrophages and also astrocytosis (Cockova et al., 2021; Yi et al., 2021; Sun Z. et al., 2022; Sun J. et al., 2022; Wang et al., 2022).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Cockova et al., 2021
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- Authors
- Cockova, Z., Honc, O., Telensky, P., Olsen, M. J., & Novotny, J.
- Affiliations
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic
- Midwestern University (US)
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-09-07
- Volume
- 12
- Issue
- 20
- Pages
- 3818-3828
- ISSN
- 1948-7193 (ISSN-L)
- OpenAlex
- W3198600441
- Cited by
- 34
- References
- 52
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 9 · 2023: 8 · 2022: 6 · 2021: 1
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- ACS Chemical Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministerstvo ??kolstv??, Ml??de??e a T??lov??chovy (LQ1605)
- Univerzita Karlova v Praze (SVV-260571/2020)
- Grantov?? Agentura, Univerzita Karlova (1320218)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Alzheimer's disease, streptozotocin, astrocytes, mitochondrial dysfunction, FTO, N6-methyladenosine, m6A demethylation, YTHDF1, oxidative stress, apoptosis, glial fibrillary acidic protein, neuroinflammation, astrocyte survival
- MeSH terms
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Adenosine, Astrocytes, Humans, Mitochondria, Streptozocin
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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