Konstantinos Lekkos, Zhilian Hu, Phong D. Nguyen, Hessel Honkoop, Esra Sengul, Rita Alonaizan, Jana Koth, Jun Ying, Madeleine E. Lemieux, Alisha Kenward, Sean D. 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 González‐Rosa, Jeroen Bakkers, Mathilda T.M. Mommersteeg
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.