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| Item Type: | Article |
|---|---|
| Title: | Oxidative phosphorylation is required for cardiomyocyte re-differentiation and long-term fish heart regeneration |
| Creators: |
Lekkos, Konstantinos, Hu, Zhilian, Nguyen, Phong D., Honkoop, Hessel, Sengul, Esra, Alonaizan, Rita, Koth, Jana, Ying, Jun, Lemieux, Madeleine E., Kenward, Alisha, Keeley, Sean, Spanjaard, Bastiaan  ORCID: https://orcid.org/0000-0003-1309-8839, Kennedy, Brett W.C., Sun, Xin, Banecki, Katherine, Potts, Helen G., Ruggiero, Gennaro, Montgomery, James, Panáková, Daniela ORCID: https://orcid.org/0000-0002-8739-6225, Junker, Jan Philipp ORCID: https://orcid.org/0000-0002-2826-8290, Heather, Lisa C., Wang, Xiaonan, Gonzalez-Rosa, Juan Manuel, Bakkers, Jeroen and Mommersteeg, Mathilda T.M.
|
| Abstract: | 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. |
| Keywords: | Cardiac Myocyte, Cell Differentiation, Cell Proliferation, Energy Metabolism, Glycolysis, Malates, Oxidative Phosphorylation, Regeneration, Sarcomeres, Time Factors, Animals, Zebrafish |
| Source: | Nature Cardiovascular Research |
| ISSN: | 2731-0590 |
| Publisher: | Springer Nature |
| Volume: | 4 |
| Number: | 10 |
| Page Range: | 1363-1380 |
| Date: | October 2025 |
| Official Publication: | https://doi.org/10.1038/s44161-025-00718-x |
| PubMed: | View item in PubMed |
| Related to: |
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