Parkin促进MCL-1的泛素化降解

Parkin is an E3 ubiquitin ligase that typically exists in an inactive form in the cytoplasm. Upon mitochondrial damage, it is phosphorylated and activated by PINK1, translocates to mitochondria, and participates in the mitophagy process. MCL-1, a critical anti-apoptotic protein of the BCL-2 family, is tightly regulated by the ubiquitin-proteasome system. Our experimental results demonstrate that mitochondrial damage induced by CCCP treatment significantly reduces MCL-1 protein levels, and this degradation depends on the proteasomal pathway. Further studies reveal that Parkin phosphorylation and activation are essential for MCL-1 degradation, whereas the absence of Parkin markedly suppresses this process. Finally, we found that Parkin directly interacts with MCL-1 and promotes its ubiquitination under CCCP-induced mitochondrial depolarization. These findings uncover a novel mechanism by which Parkin regulates cell death through ubiquitin-mediated degradation of MCL-1, providing a potential theoretical basis for MCL-1-targeted cancer therapies.