Rasmussen Megan L, Taneja Nilay, Neininger Abigail C, Wang Lili, Robertson Gabriella L, Riffle Stellan N, Shi Linzheng, Knollmann Bjorn C, Burnette Dylan T, Gama Vivian
Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Arrhythmia Research and Therapeutics, Department of Medicine, Nashville, TN 37232, USA.
iScience. 2020 Apr 24;23(4):101015. doi: 10.1016/j.isci.2020.101015. Epub 2020 Mar 30.
MCL-1 is a well-characterized inhibitor of cell death that has also been shown to be a regulator of mitochondrial dynamics in human pluripotent stem cells. We used cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) to uncover whether MCL-1 is crucial for cardiac function and survival. Inhibition of MCL-1 by BH3 mimetics resulted in the disruption of mitochondrial morphology and dynamics as well as disorganization of the actin cytoskeleton. Interfering with MCL-1 function affects the homeostatic proximity of DRP-1 and MCL-1 at the outer mitochondrial membrane, resulting in decreased functionality of hiPSC-CMs. Cardiomyocytes display abnormal cardiac performance even after caspase inhibition, supporting a nonapoptotic activity of MCL-1 in hiPSC-CMs. BH3 mimetics targeting MCL-1 are promising anti-tumor therapeutics. Progression toward using BCL-2 family inhibitors, especially targeting MCL-1, depends on understanding its canonical function not only in preventing apoptosis but also in the maintenance of mitochondrial dynamics and function.
MCL-1是一种已被充分表征的细胞死亡抑制剂，同时也被证明是人类多能干细胞中线粒体动力学的调节因子。我们利用源自人诱导多能干细胞的心肌细胞（hiPSC-CMs）来探究MCL-1对心脏功能和存活是否至关重要。BH3模拟物对MCL-1的抑制导致线粒体形态和动力学的破坏以及肌动蛋白细胞骨架的紊乱。干扰MCL-1功能会影响线粒体外膜上DRP-1和MCL-1的稳态接近度，从而导致hiPSC-CMs功能下降。即使在抑制半胱天冬酶后，心肌细胞仍表现出异常的心脏性能，这支持了MCL-1在hiPSC-CMs中的非凋亡活性。靶向MCL-1的BH3模拟物是很有前景的抗肿瘤治疗药物。向使用BCL-2家族抑制剂（尤其是靶向MCL-1的抑制剂）迈进，取决于不仅要了解其在预防细胞凋亡方面的经典功能，还要了解其在维持线粒体动力学和功能方面的作用。
