Loss of PINK1 promotes the expansion of hematopoietic cells via upregulating autophagy

Abstract PTEN-induced putative kinase 1 (PINK1) is a well-characterized regulator of mitochondrial quality control through mitophagy and its mutations are associated with recessive Parkinson’s disease. However, little is known about its functions in normal and malignant hematopoiesis in vertebrates. Here we aim to unravel the roles of PINK1 in definitive hematopoiesis and its underlying mechanisms using zebrafish (Danio rerio). In this study, we utilized CRISPR/Cas9 system to generate pink1 knockout zebrafish model and PINK1-deficient leukemia cell line. We found that pink1 deficiency activated autophagy in hematopoietic cells and promoted definitive hematopoiesis in zebrafish embryos, which can be alleviated by canonical autophagy inhibition. Further, the proteomic and metabolic analysis revealed an elevated expression of cell proliferation markers and enhanced respiration in pink1-deficient zebrafish embryos. On the other hand, PINK1 deficiency also induced autophagy and cell proliferation in human leukemic cells. Therefore, our findings demonstrated that PINK1 functions as a negative regulator of normal and malignant hematopoiesis through the autophagy-mediated pathway.