m6A–Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration

• m 6 A RNA modification is a critical regulator of mitochondrial gene expression and function • Epitranscriptomic control links nuclear RNA regulation to mitochondrial bioenergetics and stress responses. • m 6 A machinery modulates mitochondrial dynamics, mitophagy, and apoptosis pathways. • Dysregulated m 6 A signaling contributes to mitochondrial dysfunction in neurodegenerative diseases. • Targeting m 6 A regulators represents a promising therapeutic strategy to restore mitochondrial homeostasis. Mitochondrial dysfunction is a common pathology of neurodegenerative diseases, which contributes to neuronal vulnerability via excessive oxidative stress, impaired bioenergetics, and dysregulated apoptosis. Emerging studies highlighted the critical role of epitranscriptomic RNA modifications, particularly N 6 -methyladenosine (m 6 A), in mitochondrial gene expression regulation and cellular stress responses. m 6 A modifications are installed by methyltransferases (“writers,” METTL3/METTL14), recognized by readers proteins (YTH domain family proteins, IGF2BPs), and removed by demethylases (“erasers,” FTO, ALKBH5), collectively orchestrating mRNA splicing, localization, stability, and translation. Recent evidence demonstrates that m 6 A modifications modulate both nuclear-encoded and mitochondrially encoded transcripts and regulate key mitochondrial processes, including fission/fusion dynamics, oxidative phosphorylation, mitophagy, and apoptosis. Dysregulation of m 6 A machinery disrupts mitochondrial homeostasis, exacerbates oxidative stress and neuroinflammation, and promotes neuronal loss. Importantly, pharmacological or genetic modulation of m 6 A regulators can restore mitochondrial function, inhibit caspase activation, and dampen pro-inflammatory signaling, underscoring their therapeutic potential. This review consolidates current insights into mitochondrial epitranscriptomics, emphasizing how m 6 A modifications act as central regulators of mitochondrial stress responses and neurodegeneration.