RT Journal Article
SR Electronic
T1 MCL-1 inhibition by selective BH3 mimetics disrupts mitochondrial dynamics in iPSC-derived cardiomyocytes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 743922
DO 10.1101/743922
A1 Megan L. Rasmussen
A1 Nilay Taneja
A1 Abigail C. Neininger
A1 Lili Wang
A1 Linzheng Shi
A1 Bjorn C. Knollmann
A1 Dylan T. Burnette
A1 Vivian Gama
YR 2019
UL http://biorxiv.org/content/early/2019/08/22/743922.abstract
AB 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.