Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells

Abstract

Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or Mdivi-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with Mdivi-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient-specific cardiac regenerative medicine.

Targeted OMA1 therapies for cancer

“…[139][140][141] Changes in the dynamic mitochondrial network can also influence the identity, self-renewal capacity and commitment of stem cells, which reinforces the functional connection between morphology and metabolism, and which likely has implications for cancer (stem) cells as well. [142][143][144][145] Similar changes in the mitochondrial morphology have been observed also in T lymphocytes upon activation. Memory T cells on the other hand are quiescent, depend on oxidative phosphorylation, and hence showed a more fused morphology.…”

“…Interestingly, cancer cells and stem cells share the same energy metabolism and hence share a similar mitochondrial morphology . Changes in the dynamic mitochondrial network can also influence the identity, self‐renewal capacity and commitment of stem cells, which reinforces the functional connection between morphology and metabolism, and which likely has implications for cancer (stem) cells as well . Similar changes in the mitochondrial morphology have been observed also in T lymphocytes upon activation.…”

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

“…Further, we confirmed that pharmacological inhibition of Drp1 with Mdivi-1, a small molecule inhibitor of Drp1 (Bordt et al, 2017;Hoque et al, 2018) also markedly inhibited mitochondrial fission induced by chronic Ang II stimulation ( Fig 7C). Correspondingly, the mtROS production was also reduced obviously in si-Drp1-transfected ( Fig 7B) or…”

A novel role for Myosin-Va in mitochondrial fission

“…, IFN225,26 and Drp146 .Intriguingly, likewise for myosin-Va knockdown, Drp1 knockdown has also been shown to result in diminished tumorigenesis and features, such as increased OXPHOS and low clonogenic ability4,5,47 .Our data show that myosin-Va interacts with Spire1C and overexpression of Spire1C increases myosin-Va localization to mitochondria. Recently, non-mitochondrial Spire splice isoforms have been shown to interact with myosin-V motors32 .…”