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

Abstract

AbstractMaintaining 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 Alzheimer’s disease (AD). Here we report thatlncMtDloop, a lncRNA originating from the mtDNA D-loop, upholds mitochondrial homeostasis.LncMtDloopdemonstrates an affinity for mitochondrial transcription factor A (TFAM), thereby facilitating TFAM’s recruitment to mtDNA promoters and enhancing gene transcription. We further observed decreasedlncMtDloopexpression in the brains of human AD patients and 3xTg mice. Through the introduction of allotropiclncMtDloopwith the 3’UTR ofMRPS12, 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 intolncMtDloopas a regulator of mitochondrial homeostasis, shedding light on a perspective regarding its contribution to Alzheimer’s pathogenesis.