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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Alzheimer Disease*/genetics ; Alzheimer Disease*/metabolism ; Alzheimer Disease*/pathology ; Mitochondria*/metabolism ; Mitochondria*/genetics ; RNA, Long Noncoding*/genetics ; RNA, Long Noncoding*/metabolism ; Transcription, Genetic* ; Mitochondrial Proteins*/genetics ; Mitochondrial Proteins*/metabolism; Animals ; Humans ; Mice ; Disease Models, Animal ; Transcription Factors/metabolism ; Transcription Factors/genetics ; RNA, Mitochondrial/genetics ; RNA, Mitochondrial/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Mice, Transgenic ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism

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.
Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests.
(© 2024. The Author(s).)

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91649119 MOST | National Natural Science Foundation of China (NSFC); 92049105 MOST | National Natural Science Foundation of China (NSFC); 81821092 MOST | National Natural Science Foundation of China (NSFC); 8240460 MOST | National Natural Science Foundation of China (NSFC); AARF-17-531566 Alzheimer's Association (AA); 2015CB755605 Ministry of Science and Technology of the People's Republic of China (MOST); BMU2019YJ001 PKU | Peking University Health Science Center (PKUHSC); E039030401 | Applied Basic Research Key Project of Yunnan Province (Applied Basic Research Key Project of Yunnan); GRF16100219 The Hong Kong Research Grants Council (RGC)-General Research Fund (GRF); GRF16100718 The Hong Kong Research Grants Council (RGC)-General Research Fund (GRF); Ref. 133 CUHK-Improvement on Competitiveness in Hiring New Faculties Funding Scheme

Keywords: lncMtDloop; Alzheimer’s Disease; Mitochondrial Homeostasis; TFAM; mtDNA

0 (RNA, Long Noncoding)
0 (Mitochondrial Proteins)
0 (Transcription Factors)
0 (RNA, Mitochondrial)
0 (DNA-Binding Proteins)
0 (DNA, Mitochondrial)

Date Created: 20241018 Date Completed: 20241202 Latest Revision: 20241205

20250114

PMC11612450

10.1038/s44318-024-00270-7

39424953