Interplay between RNA m6A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) involves amyloid-β aggregation, tau hyperphosphorylation and mitochondrial dysfunction with defective mitophagy. Emerging evidence implicates RNA N6-methyladenosine (m6A) modification and transglutaminase 2 (TG2) as critical regulators of mitochondrial quality control in AD. Downregulation of METTL3/METTL14 and upregulation of fat mass and obesity-associated protein reduce m6A methylation, impair PTEN-induced putative kinase 1/Parkinson protein 2-mediated mitophagy and promote reactive oxygen species accumulation and synaptic loss. Conversely, TG2 overexpression exacerbates mitochondrial stress by crosslinking Aβ and tau, disturbing dynamin-related protein 1- and mitochondrial fission 1 protein-mediated dynamics and suppressing mitophagy. Crosstalk between TG2-induced oxidative stress and m6A dysregulation amplifies neuronal damage. Pharmacological modulation, using TG2 inhibitors (e.g. Z-DON) and m6A enhancers (e.g. METTL3 overexpression), restores mitophagic flux and mitigates pathology in preclinical models, suggesting dual m6A-TG2 targeting as a promising disease-modifying approach in AD.