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bioRxiv · 10.1101/743922

MCL-1 inhibition by selective BH3 mimetics disrupts mitochondrial dynamics in iPSC-derived cardiomyocytes

Rasmussen, M. L.·Taneja, N.·Neininger, A. C.·Wang, L.·Shi, L.·Knollmann, B. C.·Burnette, D. T.·Gama, V.
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Abstract

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 (hPSCs). We used cardiomyocytes derived from hPSCs (hPSC-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 hPSC-CMs. BH3 mimetics targeting MCL-1 are promising anti-tumor therapeutics. Cardiomyocytes display abnormal functional cardiac performance even after caspase inhibition, supporting a non-apoptotic activity of MCL-1 in hPSC-CMs. Progression towards using BCL-2 family inhibitors, especially targeting MCL-1, depends on understanding not only its canonical function in preventing apoptosis, but also in the maintenance of mitochondrial dynamics and function.

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Rasmussen, M. L., Taneja, N., Neininger, A. C., Wang, L., Shi, L., Knollmann, B. C., Burnette, D. T., Gama, V.. 2019-08-22. MCL-1 inhibition by selective BH3 mimetics disrupts mitochondrial dynamics in iPSC-derived cardiomyocytes. https://doi.org/10.1101/743922

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