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<p>The growing population of postmenopausal women in an aging society has led to a heightened incidence of lumbar degenerative diseases (LDD). The degeneration of the vertebral endplate cartilage is considered the initial factor in LDD, but the effect of estrogen deficiency on this process remains unclear. Here we demonstrate that estrogen deficiency triggers senescence in vertebral bone marrow mesenchymal stem cells and leads to the release of extracellular vesicles (EVs), which further accelerate the senescence of endplate chondrocytes (EPCs). Mitochondrial ribosomal proteins translate key respiratory chain components and are negatively correlated with lifespan, as their downregulation extends lifespan across species. <i>MRPL1</i>, a mitochondrial ribosomal large subunit gene, is upregulated in EV mRNA cargo under estrogen deficiency. These EVs facilitate the delivery of <i>MRPL1</i> mRNA into EPCs, enhancing MRPL1 protein translation, which in turn induces cellular senescence and supernormal mitochondrial protein turnover. MRPL1 overexpression also impairs ATP synthase activity by interacting with its catalytic subunit ATP5B, leading to senescence-related mitochondrial dysfunction in EPCs. Doxycycline administration suppresses MRPL1 expression and mitochondrial translation in EPCs, and markedly alleviates endplate degeneration associated with estrogen deficiency in a rat model, thereby introducing a novel therapeutic strategy for the management of LDD.</p>

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Vertebral BMSC-EVs under estrogen deficiency drive senescence-related mitochondrial dysfunction in endplate chondrocytes via MRPL1 mRNA delivery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月7日

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  • Yiming Zhong,
  • Zhuoxin Li,
  • Haofeng Hong,
  • Zhenda Zhao,
  • Longting Chen,
  • Zihuan Yang,
  • Dongwei Fan,
  • Wanqiong Yuan,
  • Da Zou,
  • Hua Tian,
  • Chunli Song,
  • Weishi Li,
  • Huijie Leng

摘要

The growing population of postmenopausal women in an aging society has led to a heightened incidence of lumbar degenerative diseases (LDD). The degeneration of the vertebral endplate cartilage is considered the initial factor in LDD, but the effect of estrogen deficiency on this process remains unclear. Here we demonstrate that estrogen deficiency triggers senescence in vertebral bone marrow mesenchymal stem cells and leads to the release of extracellular vesicles (EVs), which further accelerate the senescence of endplate chondrocytes (EPCs). Mitochondrial ribosomal proteins translate key respiratory chain components and are negatively correlated with lifespan, as their downregulation extends lifespan across species. MRPL1, a mitochondrial ribosomal large subunit gene, is upregulated in EV mRNA cargo under estrogen deficiency. These EVs facilitate the delivery of MRPL1 mRNA into EPCs, enhancing MRPL1 protein translation, which in turn induces cellular senescence and supernormal mitochondrial protein turnover. MRPL1 overexpression also impairs ATP synthase activity by interacting with its catalytic subunit ATP5B, leading to senescence-related mitochondrial dysfunction in EPCs. Doxycycline administration suppresses MRPL1 expression and mitochondrial translation in EPCs, and markedly alleviates endplate degeneration associated with estrogen deficiency in a rat model, thereby introducing a novel therapeutic strategy for the management of LDD.