The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.

Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis Synopsis: lncMtDloop was recently identified as a noncoding RNA expressed in the brain and encoded in the mitochondria. This work characterizes how lncMtDloop functions in mitochondrial homeostasis and its implications for Alzheimer's disease (AD) pathology. RNA pull-down followed by mass spectrometry shows lncMtDloop interaction with mitochondrial transcription factor TFAM. lncMtDloop expression is lower in brains of human AD patients and in AD mouse model brains. Fusing a mitochondrial targeting sequence to the terminal end of lncMtDloop for gain-of-function studies results in lncMtDloop restoration in mitochondria of AD mouse-model brains. Expressing lncMtDloop in AD mouse models causes amelioration of AD-like pathology, of mitochondrial function and morphological abnormalities, and of behavioral deficits. By promoting TFAM binding to target DNA, the mitochondrial lncMtDloop regulates mitochondrial transcription and overall function, and ameliorates Alzheimer's disease pathology in model mice. [ABSTRACT FROM AUTHOR]