血管性認知症におけるMETTL4によるミトコンドリアDNA 6mAメチル化を介したcGAS-STING活性化による神経炎症の駆動

Vascular cognitive impairment (VCI) is strongly associated with mitochondrial dysfunction, yet the underlying molecular mechanisms connecting mitochondrial impairment to neuroinflammation remain elusive. While mitochondrial epigenetic modifications are emerging as key regulators of cellular metabolism, the role of mitochondrial DNA (mtDNA) N⁶-methyladenine (6mA) modification and its writer enzyme METTL4 in VCI pathogenesis has not been established.

Using complementary in vitro (oxygen-glucose deprivation, OGD) and in vivo (chronic cerebral hypoperfusion, CCH) models of VCI, we systematically investigated METTL4-mediated mtDNA epigenetic regulation. Approaches included RNA sequencing (RNA-seq), mitochondrial functional assays, reactive oxygen species (ROS) measurement, and comprehensive analysis of cGAS-STING-mediated neuroinflammatory responses.

We identified mitochondrial-specific enrichment of METTL4 in hippocampal neurons, with significantly elevated mtDNA 6mA levels following CCH. Mechanistically, OGD-induced METTL4 preferentially methylated the light-strand promoter region of mtDNA, leading to: (1) impaired electron transport chain (ETC) activity, (2) excessive ROS production, and (3) oxidized mtDNA leakage. These mitochondrial abnormalities robustly activated the cGAS-STING neuroinflammatory pathway. Genetic inhibition of METTL4 normalized 6mA levels, restored mitochondrial gene expression profiles, and significantly improved cognitive function in VCI models.

Our study delineates a complete METTL4-mtDNA 6mA-mitochondrial dysfunction-neuroinflammation axis in VCI pathogenesis. These findings not only provide novel insights into the epigenetic control of neuroinflammation but also position METTL4 as a promising therapeutic target for mitigating cerebrovascular-related cognitive decline.