Parkin Regulates Adiposity by Coordinating Mitophagy with Mitochondrial Biogenesis in White Adipocytes

Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis to cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA (mtDNA) content and mitochondrial function are significantly increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion robustly elevates mitochondrial biogenesis by increasing Pgc1a protein stability through mitochondrial superoxide-activated Nqo1. Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1a protein level and mtDNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1a-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders. Overall design: We studied adipose-specific Parkin knock out mouse model and AAV drived adipose Nqo1 transgenic mouse model.