Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• iScience, 2020-04, Vol.23 (4), p.101015-101015, Article 101015

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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