The Roles of Midzone and Peripheral Mitochondrial Fission in Pulmonary Arterial Hypertension

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Colpman, Pierce
Pulmonary Arterial Hypertension , Mitochondrial Dynamics , Apoptosis , Mitophagy , Cancer , Mitotic Fission , Mitochondrial Dynamics Protein of 49kDa , Mitochondrial Dynamics Protein of 51kDa , Mitochondrial fission factor , Mitochondrial Fission Protein 1 , Dynamin-Related Protein 1 , Cardiolipin , Phosphatidic Acid , Dynamin 2
Mitochondrial fission is vital for maintaining mitochondrial health, regulating cellular processes like proliferation and apoptosis. Disrupted fission is associated with development of cardiovascular diseases, including pulmonary arterial hypertension (PAH), ischemia-reperfusion injury, cardiac hypertrophy, and heart failure. PAH is characterized by unrestricted proliferation and impaired apoptosis of pulmonary artery smooth muscle cells (PASMC), resulting in an obstructive pulmonary vasculopathy. Accelerated mitotic fission, the processes of mitochondrial fission coordinated with nuclear division, contributes to the pseudoneoplastic phenotype of PAH. Inhibiting mitochondrial fission causes cell cycle arrest halting proliferation of PASMC and triggering apoptosis. Thus, inhibiting pathologic fission is a potential therapeutic strategy for hyperproliferative diseases such as PAH. Mitochondrial fission is mediated by the large GTPase, dynamin-related protein 1 (Drp1), which upon posttranslational activation translocates near the mitochondrial outer membrane (OMM) where it binds partner proteins of the OMM (Mid49, MiD51, MFF and Fis1) creating the fission apparatus that divides the mitochondrion. Recent research by Kleele et al., identified two types of mitochondrial fission, peripheral fission, associated with mitophagy, and midzone fission, linked to mitochondrial biogenesis and cellular proliferation. Drp1 is required for both forms of fission, but these processes involve different binding partners: mitochondrial fission factor (MFF) for midzone fission and fission protein 1 (Fis1) for peripheral fission. In this study, we investigate the role of MFF and Fis1 in the pathogenesis of PAH. To do so we developed Fission GPS, based on a tool called MitoMeter by Austin Lefebvre et al. MitoMeter has the capability to quantify fission events, track, and segment mitochondria, but cannot report positional data on where these fission events take place. Fission GPS allows fast, unbiased, and automated localization of mitochondrial fission in live cells segmented by MitoMeter. We gained novel insights into the spatial regulation of mitochondrial fission under cellular stress and better defined the role of MFF and Fis1 in fission in human PAH and healthy cells. Understanding the role of MFF and Fis1 in PAH provides valuable insights into mitochondrial mechanisms contributing to cellular proliferation and apoptosis. This knowledge has implications for developing targeted therapeutic interventions aimed at modulating mitochondrial fission pathways.
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