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

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.