The Mitochondrial Long Non-coding RNA LncMtloop Regulates Mitochondrial Transcription and Suppresses Alzheimer's Disease

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2024 Oct 18

PMID 39424953

Authors

Wandi Xiong

Kaiyu Xu

Jacquelyne Ka-Li Sun

Siling Liu

Baizhen Zhao

Jie Shi

Karl Herrup

Hei-Man Chow

Lin Lu

Jiali Li

Affiliations

Soon will be listed here.

Abstract

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.

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