Browsing by Subject "Mitophagy"

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    Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma.
    (Current oncology (Toronto, Ont.), 2023-03) Wu, Jian; Fan, Shengjun; Feinberg, Daniel; Wang, Xiaobei; Jabbar, Shaima; Kang, Yubin
    Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein-protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.
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    The effects of mitochondrial damaging reagents on membrane potential and mitophagy induction, with implications in neurodegeneration
    (2023-05-03) McBane, Jason
    Mitochondria are double membrane-bound organelles with established roles in metabolism, biosynthesis, and energy production. Various mitochondrial quality control mechanisms have evolved to maintain the mitochondrial network. One such mechanism is mitophagy, where damaged mitochondria are removed from the cell via autophagosome engulfment and lysosome degradation. Mutations and deficiencies in mitophagy components are linked to Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), suggesting mitochondrial regulation is vital for cellular homeostasis. As a result, research efforts have focused on understanding mitophagy by inducing the pathway using various mitochondrial damaging reagents. However, these studies have resulted in discrepancies in the literature, highlighting our gap in knowledge of the type and severity of mitochondrial damage that induces mitophagy and drives neurodegeneration. Here, I used quantitative live-cell imaging of HeLa cells to determine whether four mitochondrial damaging reagents are comparable in depolarizing the mitochondrial membrane potential and inducing mitophagy. These reagents include carbonyl cyanide m-chlorophenyl hydrazone (CCCP), valinomycin, rotenone, and deferiprone (DFP). I found that valinomycin is the most potent at uncoupling the membrane potential, and that only reagents that depolarize the membrane induce mitophagy. My results shed light on comparable and effective in vitro mitophagy-inducing damaging paradigms that could be used to further our understanding of the etiology of neurodegenerative diseases and potential therapies.