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<p>Age-related cardiac fibrosis is a key driver of heart failure and hallmark of aging whose mechanisms remain incompletely understood. Here we show elevated succinate levels in aged mice and humans drive cardiac fibrosis by enhancing fibroblast activation and collagen production. This process is mediated through succinate-dependent succinylation of PKM2 at lysine 125, promoting its transition from tetrameric to dimeric states. Using <i>SUCNR1</i><sup><i>–/–</i></sup> mice, we establish that succinate signaling through SUCNR1/GPR91 promotes PKM2 succinylation and dimerization, creating a profibrotic network associated with aging-related diastolic dysfunction. Nuclear translocation of dimeric PKM2 enables fibroblast activation through HIF-1α binding, enhancing DNA-binding affinity and upregulating fibrogenic genes. Metformin treatment suppresses fibroblast activation by reducing succinate accumulation, revealing therapeutic potential for mitigating age-related cardiac fibrosis and diastolic dysfunction. Our findings identify metabolic dysregulation as a critical target and characterize a succinate-PKM2 signaling axis whose interruption may attenuate cardiac aging.</p><p></p>

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Succinate-driven PKM2 succinylation and dimerization accelerates age-associated cardiac fibrosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月10日

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  • Ziwen Wang,
  • Ziyuan Zhang,
  • Zheng Ping,
  • Shu Yang,
  • Yaqi Li,
  • Ting Jiang,
  • Xin Zheng,
  • Qi Zhang,
  • Zhaochuan Liu,
  • Xiaoli Zhang,
  • Zhongyong Jiang,
  • Deng Li,
  • Haimei Sun,
  • Bo Wu,
  • Deshan Zhou,
  • Xuebin Cao,
  • Hanping Shi,
  • Tingyi Sun

摘要

Age-related cardiac fibrosis is a key driver of heart failure and hallmark of aging whose mechanisms remain incompletely understood. Here we show elevated succinate levels in aged mice and humans drive cardiac fibrosis by enhancing fibroblast activation and collagen production. This process is mediated through succinate-dependent succinylation of PKM2 at lysine 125, promoting its transition from tetrameric to dimeric states. Using SUCNR1–/– mice, we establish that succinate signaling through SUCNR1/GPR91 promotes PKM2 succinylation and dimerization, creating a profibrotic network associated with aging-related diastolic dysfunction. Nuclear translocation of dimeric PKM2 enables fibroblast activation through HIF-1α binding, enhancing DNA-binding affinity and upregulating fibrogenic genes. Metformin treatment suppresses fibroblast activation by reducing succinate accumulation, revealing therapeutic potential for mitigating age-related cardiac fibrosis and diastolic dysfunction. Our findings identify metabolic dysregulation as a critical target and characterize a succinate-PKM2 signaling axis whose interruption may attenuate cardiac aging.