Research Perspective Volume 4, Issue 6 pp 393—401

Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: New insight into the role of mitophagy in cell stemness

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Figure 1. Top. mdivi-1 blocks the machinery of mitochondrial fission. Mitochondria fission is crucially regulated by the activity of DRP1, which has a sequence homology with the GTPases dynamins that regulate vesicular trafficking and endocytosis. Although the exact molecular mechanism of DRP1 in the process of mitochondrial fission is still subject of debate, one of the well-accepted models is that DRP1 acts as a mechanoenzyme that self-assemble into spirals and onto lipid bilayers forming DRP1 decorated lipid tubes that undergo a large conformational change upon GTP addition resulting in membrane constriction and, therefore, mitochondrial division. DRP1 is a protein that is mainly distributed in the cytoplasm, but there is a fraction that localizes to specific points of the external mitochondrial membrane; these points mark the fission sites in dividing mitochondria. mdivi-1 [3-(2,4-Dichloro-5-methoxy-phenyl)-2-thioxo-1H-quinazolin-4-one] is a cell-permeable quinazolinone compound that inhibits DRP1 and effectively induces mitochondrial fusion into net-like structures (IC50 = 50 μmmol/L in COS cultures) in a reversible manner. mdivi-1 blocks DRP1 GTPase activity and self-assembly by an allosteric modulation-based mechanism. Bottom. mdivi-1 inhibits mitochondrial division in MEFs. MEFs were labeled with DsRed-Mito for the visualization of mitochondrial morphology. Untreated control cells showed a relatively tubular morphology that is maintained because mitochondrial fission and fusion occur in a balanced frequency, in contrast to the extremely long nets of interconnected mitochondria that collapse and aggregate after treatment with the DRP1 inhibitor mdivi-1.