TY - JOUR
T1 - Oxidative phosphorylation is required for cardiomyocyte re-differentiation and long-term fish heart regeneration
AU - Lekkos, Konstantinos
AU - Hu, Zhilian
AU - Nguyen, Phong D
AU - Honkoop, Hessel
AU - Sengul, Esra
AU - Alonaizan, Rita
AU - Koth, Jana
AU - Ying, Jun
AU - Lemieux, Madeleine E
AU - Kenward, Alisha
AU - Keeley, Sean
AU - Spanjaard, Bastiaan
AU - Kennedy, Brett W C
AU - Sun, Xin
AU - Banecki, Katherine
AU - Potts, Helen G
AU - Ruggiero, Gennaro
AU - Montgomery, James
AU - Panáková, Daniela
AU - Junker, Jan Philipp
AU - Heather, Lisa C
AU - Wang, Xiaonan
AU - Gonzalez-Rosa, Juan Manuel
AU - Bakkers, Jeroen
AU - Mommersteeg, Mathilda T M
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/10
Y1 - 2025/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105017690120
U2 - 10.1038/s44161-025-00718-x
DO - 10.1038/s44161-025-00718-x
M3 - Article
C2 - 41034455
SN - 2731-0590
VL - 4
SP - 1363
EP - 1380
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 10
ER -