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<p>Mitochondrial dysfunction is a hallmark of aging that elicits adaptive nuclear responses, yet how chromatin remodeling is coordinated under stress remains unclear. Here, we uncover a phosphorylation-dependent mechanism by which mitochondrial stress regulates the activity of the NuRD (nucleosome remodeling and deacetylase) complex via LIN-40, the <i>Caenorhabditis elegans</i> homolog of mammalian MTA proteins. Mitochondrial stress triggers dephosphorylation of LIN-40, enhancing its interaction with the transcription factor DVE-1 to activate the mitochondrial unfolded protein response (UPR<sup>mt</sup>) and chromatin remodeling. Phosphorylation of LIN-40 is mediated by p38 MAPK/PMK-3 and reversed by PP1c/GSP-2. Furthermore, the LIN-40(T654D) variant abolishes mitochondrial stress-induced lifespan extension. These findings establish a direct link between mitochondrial stress signaling and chromatin remodeling via NuRD, revealing an evolutionarily conserved strategy to coordinate cellular resilience and organismal longevity.</p>

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Mitochondrial stress orchestrates chromatin remodeling and longevity via phosphoregulation of the NuRD component LIN-40

  • 期刊论文

  • 发表日期：

    2025年8月13日

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  • Jun Zhou,
  • Di Zhu,
  • Yibing Wang,
  • Zilun Wang,
  • Ning Zhang,
  • Xiahe Huang,
  • Yiqian Zhang,
  • Yingchun Wang,
  • Xueying Wu,
  • Ye Tian

摘要

Mitochondrial dysfunction is a hallmark of aging that elicits adaptive nuclear responses, yet how chromatin remodeling is coordinated under stress remains unclear. Here, we uncover a phosphorylation-dependent mechanism by which mitochondrial stress regulates the activity of the NuRD (nucleosome remodeling and deacetylase) complex via LIN-40, the Caenorhabditis elegans homolog of mammalian MTA proteins. Mitochondrial stress triggers dephosphorylation of LIN-40, enhancing its interaction with the transcription factor DVE-1 to activate the mitochondrial unfolded protein response (UPRmt) and chromatin remodeling. Phosphorylation of LIN-40 is mediated by p38 MAPK/PMK-3 and reversed by PP1c/GSP-2. Furthermore, the LIN-40(T654D) variant abolishes mitochondrial stress-induced lifespan extension. These findings establish a direct link between mitochondrial stress signaling and chromatin remodeling via NuRD, revealing an evolutionarily conserved strategy to coordinate cellular resilience and organismal longevity.