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<p>In contrast to humans, fish can fully regenerate their hearts after cardiac injury. However, not all fish have the same regenerative potential, allowing comparative inter-species and intra-species analysis to identify the mechanisms controlling successful heart regeneration. Here we report a differential regenerative response to cardiac cryo-injury among different wild-type zebrafish strains. Correlating these data with single-cell and bulk RNA sequencing data, we identify oxidative phosphorylation (OXPHOS) as a positive regulator of long-term regenerative outcome. OXPHOS levels, driven by glycolysis through the malate-aspartate shuttle, increase as soon as cardiomyocyte proliferation decreases, and this increase is required for cardiomyocyte re-differentiation and successful long-term regeneration. Reduced upregulation of OXPHOS in <i>Astyanax mexicanus</i> cavefish results in the absence of a dynamic temporal sarcomere gene expression program during cardiomyocyte re-differentiation. These findings challenge the assumption that OXPHOS inhibits regeneration and reveal targetable pathways to enhance heart repair in humans after myocardial infarction.</p>

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Oxidative phosphorylation is required for cardiomyocyte re-differentiation and long-term fish heart regeneration

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月1日

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  • Konstantinos Lekkos,
  • Zhilian Hu,
  • Phong D. Nguyen,
  • Hessel Honkoop,
  • Esra Sengul,
  • Rita Alonaizan,
  • Jana Koth,
  • Jun Ying,
  • Madeleine E. Lemieux,
  • Alisha Kenward,
  • Sean Keeley,
  • Bastiaan Spanjaard,
  • Brett W. C. Kennedy,
  • Xin Sun,
  • Katherine Banecki,
  • Helen G. Potts,
  • Gennaro Ruggiero,
  • James Montgomery,
  • Daniela Panáková,
  • Jan Philipp Junker,
  • Lisa C. Heather,
  • Xiaonan Wang,
  • Juan Manuel Gonzalez-Rosa,
  • Jeroen Bakkers,
  • Mathilda T. M. Mommersteeg

摘要

In contrast to humans, fish can fully regenerate their hearts after cardiac injury. However, not all fish have the same regenerative potential, allowing comparative inter-species and intra-species analysis to identify the mechanisms controlling successful heart regeneration. Here we report a differential regenerative response to cardiac cryo-injury among different wild-type zebrafish strains. Correlating these data with single-cell and bulk RNA sequencing data, we identify oxidative phosphorylation (OXPHOS) as a positive regulator of long-term regenerative outcome. OXPHOS levels, driven by glycolysis through the malate-aspartate shuttle, increase as soon as cardiomyocyte proliferation decreases, and this increase is required for cardiomyocyte re-differentiation and successful long-term regeneration. Reduced upregulation of OXPHOS in Astyanax mexicanus cavefish results in the absence of a dynamic temporal sarcomere gene expression program during cardiomyocyte re-differentiation. These findings challenge the assumption that OXPHOS inhibits regeneration and reveal targetable pathways to enhance heart repair in humans after myocardial infarction.