FTO-mediated m6A demethylation regulates PGC-1α-dependent mitochondrial biogenesis to attenuate aluminum-induced neuronal senescence.

Overview

Authors: Zhaoya Jin^1,2,3, Shuai Li⁴, Jinzhu Yin⁵, Xiaoyu He^1,2,3, Ru Wang^1,2,3, Yang Liu^1,2,3, Huifang Zhang^1,2,3

Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, China
Key Laboratory of Environmental Health Impairment and Prevention in Shanxi, Taiyuan, China
MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention in Shanxi, Taiyuan, China
First Clinical Medical College, Shanxi Medical University, Taiyuan, China
Department of Neurosurgery, Datong Key Laboratory of Nervous systems Disease Prevention and Treatment for Coal Mine workers, Shanxi Health Commission Key Laboratory of Nervous System Disease Prevention and Treatment, Sinopharm Tongmei General Hospital, Datong, 037003 Shanxi China

Institutions: Shanxi Medical University (China); China National Pharmaceutical Group Corporation (China) (China)

Journal: Scientific reports, volume 16, issue 1, article 21890

Dates: received 19 July 2025; accepted 29 April 2026; published online 7 May 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41598-026-51674-w · PMID 42098356 · PMCID PMC13365551 · OpenAlex W7160563532

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: mouse (organism), cellular / molecular (subfield)

Methods: Statistics, Preprocessing, Smoothing, state filtering, decompositions, Connectivity

Keywords: Aluminum, FTO, m6A methylation, PGC-1α, Mitochondrial biogenesis, Senescence, Cell biology, Genetics, Molecular biology, Neuroscience

MeSH: Alpha-Ketoglutarate-Dependent Dioxygenase FTO*, Aluminum*, Cellular Senescence*, Neurons*, Organelle Biogenesis*, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha*, Adenosine, Animals, Cell Line, Demethylation, Epitranscriptome, Mice, Mitochondria, RNA Methylation (* major topic)

Topic: Aluminum toxicity and tolerance in plants and animals (Plant Science, Agricultural and Biological Sciences), according to OpenAlex

Funding: Key Laboratory of Neurological Disease Prevention and Treatment, Shanxi Provincial Health Commission (No. TMSYSKF2023002); Natural Science Foundation of Shanxi Province (No. 202203021211245)

Citations: not cited yet (Europe PMC); 49 references in the paper

Abstract

Aluminum (Al) exposure is increasingly recognized as a risk factor for neurodegenerative disorders; however, the epitranscriptomic mechanisms linking environmental Al toxicity to neuronal senescence and mitochondrial alterations remain poorly understood. We hypothesized that impairs mitochondrial biogenesis and may disrupt mitochondrial homeostasis through dysregulation of N6-methyladenosine (m6A) RNA modification mediated by the m6A demethylase fat mass and obesity-associated protein (FTO). HT22 mouse hippocampal neurons were exposed to aluminum maltolate (60–240 µmol/L). An FTO-overexpression model was established. MeRIP-seq and RNA-seq were performed to assess m6A and transcriptomic changes. Mitochondrial status, particularly mitochondrial biogenesis–related indicators, was evaluated via ATP and mtDNA levels. SA-β-Gal staining assessed senescence. The expression of senescence-associated markers (e.g., p16, p21, HMGA1) and mitochondrial regulatory factors (e.g., FTO, PGC-1α, NRF-1, NRF-2, TFAM) was examined by qPCR and Western blotting. Aluminum exposure globally increased m6A methylation (7,068 peaks upregulated), affecting pathways linked to senescence and neurodegeneration. PGC-1α showed increased m6A and decreased expression. Aging markers (P16, P21, HMGA1) were upregulated, while mitochondrial biogenesis–related indicators (ATP levels, mtDNA copy number, and the PGC-1α axis) were reduced, indicating impaired mitochondrial biogenesis. FTO expression was suppressed by aluminum but overexpression of FTO reversed these effects, reducing m6A levels, restoring PGC-1α expression, partially restoring mitochondrial biogenesis-related parameters, and attenuating senescence. Our findings suggest that aluminum induces neuronal senescence by inhibiting FTO, increasing m6A methylation, and downregulating PGC-1α-mediated mitochondrial biogenesis. The FTO–m6A–PGC-1α axis plays a critical role in aluminum neurotoxicity.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-51674-w.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

geo:GSE304247, at NCBI GEO; found in the text, “MeRIP-Seq and mRNA sequencing”

Data availability

The datasets generated and analyzed during the current study have been deposited in the NCBI Gene Expression Omnibus (GEO) under the accession numbers GSE304247 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304247) and GSE304248 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304248).As the datasets are currently under embargo, they are available to editors and reviewers via the following links: GSE304247 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304247): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304247&token=qbqjaqsqtlynnun. GSE304248 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304248): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304248&token=kroramqqfrshhib.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 10 keywords, 14 MeSH terms, 2 funders, 49 references.

Cite

This paper

Jin, Z., Li, S., Yin, J., He, X., Wang, R., Liu, Y., & Zhang, H. (2026). FTO-mediated m6A demethylation regulates PGC-1α-dependent mitochondrial biogenesis to attenuate aluminum-induced neuronal senescence. Scientific reports, 16(1), 21890. https://doi.org/10.1038/s41598-026-51674-w

BibTeX

@article{jin2026fto, author = {Jin, Zhaoya and Li, Shuai and Yin, Jinzhu and He, Xiaoyu and Wang, Ru and Liu, Yang and Zhang, Huifang}, title = {{FTO-mediated m6A demethylation regulates PGC-1α-dependent mitochondrial biogenesis to attenuate aluminum-induced neuronal senescence}}, journal = {Scientific reports}, year = {2026}, month = may, volume = {16}, number = {1}, pages = {21890}, publisher = {Nature Publishing Group}, issn = {2045-2322}, doi = {10.1038/s41598-026-51674-w}, url = {https://doi.org/10.1038/s41598-026-51674-w}, pmid = {42098356}, pmcid = {PMC13365551} }

RIS

TY - JOUR AU - Jin, Zhaoya AU - Li, Shuai AU - Yin, Jinzhu AU - He, Xiaoyu AU - Wang, Ru AU - Liu, Yang AU - Zhang, Huifang TI - FTO-mediated m6A demethylation regulates PGC-1α-dependent mitochondrial biogenesis to attenuate aluminum-induced neuronal senescence T2 - Scientific reports J2 - Sci Rep PY - 2026 DA - 2026/05/07 VL - 16 IS - 1 SP - 21890 SN - 2045-2322 PB - Nature Publishing Group DO - 10.1038/s41598-026-51674-w UR - https://doi.org/10.1038/s41598-026-51674-w LA - en ER -

CSL-JSON

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