Homocysteine Induced N6-methyldeoxyadenosine Modification Perturbation Elicits Mitochondria Dysfunction Contributes to the Impairment of Learning and Memory Ability caused by Early Life Stress in Rats

Mitochondrial dysfunction is the key pathological mechanism of cognitive decline, and homocysteine (Hcy) plays a vital role in modulating mitochondrial homeostasis. However, the regulating mechanism and intervention targets of Hcy-induced mitochondrial damage involved in brain impairment remain unclear. Herein, it is found that elevated Hcy levels lead to the increasement of METTL4 expression and augmentation of N6-methyldeoxyadenosine (6 mA) modification in mitochondrial DNA (mtDNA) induced by maternal separation (MS) stress. Meanwhile, mtDNA copy number and gene expression level were suppressed in the hippocampus and the binding of the mitochondrial transcription factor A (TFAM) to the mtDNA promoters can be obstructed, leading to mitochondrial dysfunction and learning and memory impairment. Thus, there was a pivotal role of mtDNA 6 mA regulated by METTL4 in Hcy mediated mitochondrial dysfunction and cognitive damage in rat exposed to early life stress, and targeted regulation of Hcy to rectify mtDNA 6 mA excess may be a strategy for developing mitochondria-focused cognitive disorders interventions.