MCL-1 Inhibition by Selective BH3 Mimetics Disrupts Mitochondrial Dynamics Causing Loss of Viability and Functionality of Human Cardiomyocytes

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 an...

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Published iniScience Vol. 23; no. 4; p. 101015
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 24.04.2020
Elsevier
Subjects
Cell Biology
Molecular Biology
Molecular Biology
Cell Biology
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Summary: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. [Display omitted] •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 inhibitors Molecular Biology; Cell Biology
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These authors contributed equally
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.101015