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Updated: Feb 17, 2026

Author Spotlight: Decoding Mitochondrial Aging
Published on: June 30, 2023
Mitochondrial double-stranded RNA drives aging-associated cognitive decline
Lixiao Zhang1, Xiang Li1, Hongdi Luo1
1State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
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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