Parkin in Metabolic Regulation and Tumor Suppression

PARK2 , which encodes the E3 ubiquitin ligase Parkin, was originally identified as a Parkinson’s disease (PD)-associated gene. Although Parkin has been extensively studied for its role in mitochondrial quality control and PD, accumulating evidence has revealed an important role of Parkin in tumor suppression. Genetic alterations of PARK2 and loss or reduced expression of Parkin are frequently observed in many types of human cancers and are often associated with poor clinical outcomes. Furthermore, Parkin deficiency promotes tumor progression in various experimental models. However, the molecular mechanisms underlying the tumor-suppressive function of Parkin remain incompletely understood. Metabolic reprogramming is a hallmark of cancer that plays a key role in tumor progression by meeting the energetic and biosynthetic demands of cancer cells and facilitating their adaptation to the tumor microenvironment. Emerging evidence indicates that metabolic regulation represents an important mechanism by which Parkin exerts its tumor-suppressive function. In addition to its well-established role in mitophagy, Parkin regulates diverse metabolic pathways. Recent studies have implicated Parkin in the regulation of mitochondrial function, cellular redox homeostasis, glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic pathways. Dysregulation of these processes following Parkin deficiency can promote metabolic reprogramming that supports cancer cell proliferation, survival, and cancer progression. In this review, we summarize recent advances in understanding the roles and mechanisms of Parkin in cancer metabolism and how Parkin-mediated metabolic regulation contributes to tumor suppression. We further discuss the potential therapeutic opportunities arising from the metabolic vulnerabilities associated with Parkin deficiency.