Mitophagy is a selective form of autophagy for clearance of damaged mitochondria via the autophagy-lysosome pathway. Among various mitophagy regulatory mechanisms, PINK1, a protein kinase, and Parkin, an E3 ligase, are two critical players, with important implications in neurodegenerative disorders such as Parkinson's disease (PD). In this presentation, I will cover some of our recent work, including (1) Identification of a non-canonical function of SMAD3 as a novel nuclear transcription factor of PINK1; (2) effect of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in glycolysis, on PINK1; (3) Establishing O-N-acetylgalactosamine (O-GalNAc) of PINK1 as a novel form of post-translational modifications in control of PINK1 activation in response to acute mitochondrial damage. Our results thus provide a deeper insight into the molecular mechanisms in control of PINK1, the guardian of mitochondria and lay foundation for development of novel interventional strategies in PINK1 and mitophagy-related human diseases such as neurodegeneration and cancer.