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  • 标题:MCL-1 Inhibition by Selective BH3 Mimetics Disrupts Mitochondrial Dynamics Causing Loss of Viability and Functionality of Human Cardiomyocytes
  • 本地全文:下载
  • 作者:Megan L. Rasmussen ; Nilay Taneja ; Abigail C. Neininger
  • 期刊名称:iScience
  • 印刷版ISSN:2589-0042
  • 出版年度:2020
  • 卷号:23
  • 期号:4
  • 页码:1-40
  • DOI:10.1016/j.isci.2020.101015
  • 语种:English
  • 出版社:Elsevier
  • 摘要:SummaryMCL-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.Graphical AbstractDisplay OmittedHighlights•BH3 mimetics targeting MCL-1 disrupt the mitochondrial network of human iPSC-CMs•The BH3-mimetic-mediated effects on mitochondrial dynamics are DRP-1-dependent•Targeting MCL-1 affects the survival and function of human cardiomyocytes•Human iPSC-derived cardiomyocytes can be used to reveal toxicity of MCL-1 inhibitorsMolecular Biology; Cell Biology
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