m⁶A-Mediated epitranscriptomic control of mitochondrial dysfunction in neurodegeneration

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 N⁶-methyladenosine (m⁶A), in mitochondrial gene expression regulation and cellular stress responses. m⁶A modifications are installed by methyltransferases ("writers," METTL3/METTL14), recognized by reader 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 m⁶A 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 m⁶A machinery disrupts mitochondrial homeostasis, exacerbates oxidative stress and neuroinflammation, and promotes neuronal loss. Importantly, pharmacological or genetic modulation of m⁶A 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 m⁶A modifications act as central regulators of mitochondrial stress responses and neurodegeneration.