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<p>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 (<i>Sec61a1</i><sup>Tg</sup>) 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.</p>

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Mitochondrial double-stranded RNA drives aging-associated cognitive decline

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • 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

摘要

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.