Mitochondrial double-stranded RNA drives aging-associated cognitive decline

IF 31.1 1区生物学 Q1 CELL BIOLOGY

Cell Research Pub Date : 2026-02-16 DOI:10.1038/s41422-026-01224-w

Lixiao Zhang, Xiang Li, Hongdi Luo, Yujia Huo, Guangkeng Zhou, Pengcheng Wang, Sipeng Wu, Xinyong Lin, Kai Dai, Jiahao Shi, Zebao Wang, Jiaxin Xu, Renjian Li, Siyi Chen, Zhe Sun, Chunlin Zhao, Zizhuo Zhou, Zhenhong Wang, Chensi Liang, Jun Zhu, Xingjun Chen, Jintao Luo, Yong Yu, Zhirong Zhang, Geng Wang

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Abstract

Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER–mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA). This pathway is activated in aged wild-type mice, Alzheimer’s disease patients, and 5×FAD mice. Tissue-specific overexpression of Sec61a1 in the mouse cortex (Sec61a1Tg) is sufficient to induce cognitive decline without affecting motor activity. Knockdown of Sec61a1 or Mavs ablates mt-dsRNA-mediated innate immune signaling and alleviates cognitive decline in naturally aging wild-type mice. These results reveal a molecular mechanism of aging- and disease-associated cognitive decline and provide a potential therapeutic tool for intervention.

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线粒体双链RNA驱动衰老相关的认知能力下降。

衰老是认知能力下降的主要原因。尽管进行了广泛的研究，但导致衰老相关认知能力下降的分子机制仍不清楚。在这里，我们描述了SEC61A1的一种不依赖于蛋白酶的功能，以及它与衰老相关的认知能力下降的关系。SEC61A1调节er -线粒体接触位点，影响线粒体DNA和RNA合成，进而导致线粒体双链RNA （mt-dsRNA）介导的先天免疫信号的改变。这一途径在老年野生型小鼠、阿尔茨海默病患者和5×FAD小鼠中被激活。小鼠皮层组织特异性过表达Sec61a1 （Sec61a1Tg）足以诱导认知能力下降而不影响运动活动。敲低Sec61a1或Mavs可减弱mt- dsrna介导的先天免疫信号，减轻自然衰老野生型小鼠的认知能力下降。这些结果揭示了衰老和疾病相关认知能力下降的分子机制，并为干预提供了潜在的治疗工具。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Research 生物-细胞生物学

CiteScore

53.90

自引率

0.70%

发文量

2420

审稿时长

2.3 months

期刊介绍： Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.