At the mitochondrial surface, Drp1 is thought to wrap around the mitochondria to induce fission powered by its GTPase activity ( Smirnova et al., 2001). In mammalian cells, mitochondrial fusion is regulated by mitofusin-1 and -2 (MFN-1/2) and optic atrophy 1 (OPA1), whereas mitochondrial fission is controlled by dynamin-1-related protein, Drp1 ( Chan, 2006a Scott and Youle, 2010) and its mitochondrial adaptors such as Fis1, Mff and MIEF1 ( Otera et al., 2010 Palmer et al., 2011 Zhao et al., 2011).ĭrp1 is primarily found in the cytosol, but it translocates from the cytosol to the mitochondrial surface in response to various cellular stimuli to regulate mitochondrial morphology ( Chang and Blackstone, 2010). The two opposing processes, fusion and fission, are controlled by evolutionarily conserved large GTPases that belong to the dynamin family of proteins. Defects in either fusion or fission limit mitochondrial motility, decrease energy production and increase oxidative stress, thereby promoting cell dysfunction and death ( Jahani-Asl et al., 2010 Scott and Youle, 2010). This dynamic process controls not only mitochondrial morphology, but also the subcellular location and function of mitochondria. Mitochondria are organized in a highly dynamic tubular network that is continuously reshaped by opposing processes of fusion and fission ( Chan, 2006b). Taken together, our findings suggest that P110, as a selective peptide inhibitor of Drp1, might be useful for the treatment of diseases in which excessive mitochondrial fission and mitochondrial dysfunction occur. Finally, P110 required the presence of Drp1 to inhibit mitochondrial fission under oxidative stress conditions. We also found that P110 treatment appears to have minimal effects on mitochondrial fission and cell viability under basal conditions. P110 increased neuronal cell viability by reducing apoptosis and autophagic cell death, and reduced neurite loss of primary dopaminergic neurons in this PD cell culture model. Furthermore, using a model of Parkinson's disease (PD) in culture, we demonstrated that P110 is neuroprotective by inhibiting mitochondrial fragmentation and reactive oxygen species (ROS) production and subsequently improving mitochondrial membrane potential and mitochondrial integrity. P110 inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons, whereas it has no effect on the interaction between Drp1 and other mitochondrial adaptors, as demonstrated by co-immunoprecipitation. Using a rational approach, we designed a novel and selective peptide inhibitor, P110, of excessive mitochondrial fission. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools in addition to potential leads for drug development. Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases.
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