Institute of Biomedical Sciences, Academia Sinica, Taiwan.
FEBS J. 2022 Apr;289(7):1897-1910. doi: 10.1111/febs.16263. Epub 2021 Nov 19.
Loss of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) in cardiomyocytes results in energy shortage and heart failure. We aim to understand the intracellular signal pathway and extracellular factors regulating Drp1 phosphorylation and mitochondrial morphology and function in cardiomyocytes. We found cyclic mechanical stretching induced mitochondrial fission through Drp1 and focal adhesion kinase (FAK) in neonatal rat ventricular myocytes (NRVMs). FAK regulated phosphorylation of Drp1 and mitochondrial Drp1 levels. Extracellular fibronectin activated Drp1 and caused mitochondrial fission through FAK and extracellular signal-regulated kinase 1/2 (ERK1/2). Fibronectin increased NRVMs oxygen consumption rate and ATP content via FAK-ERK1/2-Drp1. Inhibition of the FAK-ERK1/2-Drp1 pathway caused cellular energy shortage. In addition, the FAK-ERK1/2-Drp1 pathway was rapidly activated by adrenergic agonists and contributed to agonists-stimulated NRVMs respiration. Interestingly, fibronectin limited the adrenergic agonists-induced NRVMs respiration by restricting phosphorylation of Drp1. Our results suggest that extracellular fibronectin and adrenergic stimulations use the FAK-ERK1/2-Drp1 pathway to regulate mitochondrial morphology and function in cardiomyocytes.
线粒体裂变酶相关蛋白 1（Drp1）在心肌细胞中的缺失会导致能量短缺和心力衰竭。我们旨在了解调节心肌细胞中 Drp1 磷酸化和线粒体形态和功能的细胞内信号通路和细胞外因子。我们发现，周期性机械拉伸通过 Drp1 和黏着斑激酶（FAK）诱导新生大鼠心室肌细胞（NRVM）中的线粒体裂变。FAK 调节 Drp1 的磷酸化和线粒体 Drp1 水平。细胞外纤维连接蛋白通过 FAK 和细胞外信号调节激酶 1/2（ERK1/2）激活 Drp1 并导致线粒体裂变。纤维连接蛋白通过 FAK-ERK1/2-Drp1 增加 NRVMs 的耗氧量和 ATP 含量。FAK-ERK1/2-Drp1 通路的抑制会导致细胞能量短缺。此外，儿茶酚胺激动剂可快速激活 FAK-ERK1/2-Drp1 通路，促进激动剂刺激的 NRVMs 呼吸。有趣的是，纤维连接蛋白通过限制 Drp1 的磷酸化来限制肾上腺素能激动剂诱导的 NRVMs 呼吸。我们的结果表明，细胞外纤维连接蛋白和肾上腺素能刺激通过 FAK-ERK1/2-Drp1 通路调节心肌细胞中线粒体的形态和功能。
