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

IF 10.8 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
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
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引用次数: 0

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.

氧化磷酸化是心肌细胞再分化和长期心脏再生所必需的。
与人类不同,鱼在心脏受伤后可以完全再生心脏。然而,并不是所有的鱼类都具有相同的再生潜力,因此可以通过物种间和物种内的比较分析来确定控制成功心脏再生的机制。在这里,我们报告了不同野生型斑马鱼株对心脏低温损伤的不同再生反应。将这些数据与单细胞和大量RNA测序数据相关联,我们确定氧化磷酸化(OXPHOS)是长期再生结果的积极调节因子。在苹果酸-天冬氨酸穿梭的糖酵解作用下,OXPHOS水平随着心肌细胞增殖的减少而增加,这种增加是心肌细胞再分化和成功的长期再生所必需的。在Astyanax mexicanus洞穴鱼中,OXPHOS上调的减少导致心肌细胞再分化过程中动态颞肌节基因表达程序的缺失。这些发现挑战了OXPHOS抑制再生的假设,并揭示了心肌梗死后增强人类心脏修复的可靶向途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
5.70
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