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Mitochondrial double-stranded RNA drives aging-associated cognitive decline

Lixiao Zhang^1,† , Xiang Li^1,† , Hongdi Luo^1,† , Yujia Huo¹ , Guangkeng Zhou¹ , Pengcheng Wang^1,2 , Sipeng Wu¹ , Xinyong Lin¹ , Kai Dai³ , Jiahao Shi¹ , Zebao Wang¹ , Jiaxin Xu¹ , Renjian Li¹ , Siyi Chen¹ , Zhe Sun¹ , Chunlin Zhao¹ , Zizhuo Zhou¹ , Zhenhong Wang¹ , Chensi Liang⁴ , Jun Zhu¹ , Xingjun Chen¹ , Jintao Luo¹ , Yong Yu¹ , Zhirong Zhang^1,* , Geng Wang^1,5,*

¹State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
²Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Fujian Branch of National Clinical Research Center for Cardiovascular Disease, Xiamen, Fujian, China
³Department of Neurology, Wenzhou Central Hospital & Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, China
⁴Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, China
⁵Department of Oncology, Xiang’an Hospital of Xiamen University, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
^†These authors contributed equally: Lixiao Zhang, Xiang Li, Hongdi Luo
* Correspondence: Zhirong Zhang(21620210156751@stu.xmu.edu.cn)Geng Wang(wangengfuan@xmu.edu.cn)

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.

https://doi.org/10.1038/s41422-026-01224-w

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