Department of Medical, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
Department of Medical Experiment Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
Lab Invest. 2022 Sep;102(9):979-988. doi: 10.1038/s41374-022-00787-7. Epub 2022 Apr 29.
Abnormal Drp1 activation and subsequent excessive mitochondrial fission play a critical role in ischemia-reperfusion injury (I/RI). Although fibroblast growth factor 21 (FGF21) protects organs against I/RI and regulates metabolism, which indicates that FGF21 is involved in mitochondria homeostasis, the detailed mechanism remains unclear. Herein, we investigated whether FGF21 had an effect on Drp1 activation during skeletal muscle I/RI. Drp1 phosphorylation and its translocation to mitochondria, as regulated by FGF21, was examined in mouse and C2C12 cell I/RI models. Mice overexpressing FGF21 displayed alleviation of serum index, histological lesions and apoptosis levels. Moreover, FGF21 markedly decreased cyclin-dependent kinase 1 (CDK1) and Drp1 phosphorylation at Ser616, accompanied by reduced accumulation in mitochondria. In parallel in vitro studies, cells with FGF21 knockdown displayed enhanced Drp1 activation, and the reverse effect was found when FGF21 was added. More importantly, FGF21 attenuated mitochondrial fission with linear mitochondria rather than fragmented mitochondria. Furthermore, a CDK1 inhibitor reduced Drp1 activation and mitochondrial fission due to FGF21 knockdown. This study shows that FGF21 inhibits Drp1 activation to protect mitochondria from fission, thereby rescuing cells from I/RI-induced apoptosis. Our findings may provide a new therapeutic approach to ameliorate skeletal muscle I/RI.
异常的 Drp1 激活及随后的过度线粒体分裂在缺血再灌注损伤（I/RI）中起着关键作用。尽管成纤维细胞生长因子 21（FGF21）可保护器官免受 I/RI 影响并调节代谢，这表明 FGF21 参与了线粒体的动态平衡，但具体机制尚不清楚。在此，我们研究了 FGF21 是否会影响骨骼肌 I/RI 过程中的 Drp1 激活。在鼠和 C2C12 细胞 I/RI 模型中，检测了 FGF21 对 Drp1 磷酸化及其向线粒体易位的调节作用。过表达 FGF21 的小鼠显示血清指标、组织学损伤和细胞凋亡水平的改善。此外，FGF21 明显降低了 CDK1 和 Drp1 在 Ser616 的磷酸化，伴随着在线粒体中的积累减少。在平行的体外研究中，敲低 FGF21 的细胞显示出 Drp1 激活增强，而添加 FGF21 则会产生相反的效果。更重要的是，FGF21 减轻了线粒体分裂，使线粒体呈线性而非碎片化。此外，CDK1 抑制剂可减少由于 FGF21 敲低导致的 Drp1 激活和线粒体分裂。这项研究表明，FGF21 通过抑制 Drp1 激活来保护线粒体免受分裂，从而挽救细胞免受 I/RI 诱导的凋亡。我们的研究结果可能为改善骨骼肌 I/RI 提供一种新的治疗方法。
