Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice.
Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice.
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DOI：
10.1016/j.jbc.2021.100825
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Ross RS
中科院分区：
文献类型：
--
作者：
Cho Y;Tachibana S;Lam K;Arita Y;Khosrowjerdi S;Zhang O;Liang A;Li R;Andreyev A;Murphy AN;Ross RS
心脏的正常收缩功能依赖于心肌细胞持续可靠地产生ATP。心脏能量代谢失调可导致心脏发育不成熟，破坏成人心肌适应压力的能力，可能导致心力衰竭。此外，异常线粒体功能的恢复可以对心功能障碍产生有益的影响。之前，我们发现了一种名为Perm1 （PGC-1和雌激素相关受体（ERR）诱导的调节因子，肌肉1）的新蛋白，它富含骨骼和心肌线粒体，并由PGC-1（过氧化物酶体增殖体激活受体γ辅激活因子1）和ERR进行转录调节。人们对Perm1在心脏中的作用知之甚少，本文对其进行了研究。我们利用细胞培养、小鼠模型和人体组织来研究其表达和转录控制，以及它在其他因子转录中的作用。关键的是，我们测试了Perm1在心肌细胞线粒体功能中的作用及其保护心肌细胞免受应激性损伤的能力。我们的研究表明，在小鼠心脏发生过程中，Perm1的表达增加，表明Perm1与PGC-1α相互作用，增强PGC-1和ERR的激活，增加线粒体DNA拷贝数，增强培养的新生小鼠心肌细胞的氧化能力。此外，我们发现Perm1减少了由于缺氧和再氧诱导的应激而产生的细胞损伤，并减轻了心肌细胞的细胞死亡。综上所述，我们的研究结果表明，Perm1促进了小鼠心肌细胞线粒体的生物发生。未来的研究可以评估Perm1作为一种新的治疗方法用于恢复缺血性损伤引起的心功能障碍的潜力。
Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.
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DOI：
10.1073/pnas.0603615103
发表时间：
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影响因子：
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作者：
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发表时间：
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影响因子：
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