The mtDNA-derived lncMtDloop promotes mitochondrial homeostasis maintenance and implications in AD

Maintaining mitochondrial homeostasis stands as a critical factor for cell survival and the health of organisms, as evidenced by the links between mitochondrial dysfunction and a spectrum of diseases, including Alzheimers disease (AD). Here we report that lncMtDloop, a lncRNA originating from the mtDNA D-loop, upholds mitochondrial homeostasis. LncMtDloop demonstrates an affinity for mitochondrial transcription factor A (TFAM), thereby facilitating TFAMs recruitment to mtDNA promoters and enhancing gene transcription. We further observed decreased lncMtDloop expression in the brains of human AD patients and 3xTg mice. Through the introduction of allotropic lncMtDloop with the 3UTR of MRPS12, a significant improvement in mitochondrial homeostasis and a concurrent amelioration of AD-like pathology were found, which exerts a positive influence on synaptic plasticity and behavioral deficits observed in AD mice. Our study provides mechanistic insights into lncMtDloop as a regulator of mitochondrial homeostasis, shedding light on a perspective regarding its contribution to Alzheimers pathogenesis.