Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem and progenitor cells

Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics via promotion of microtubule catastrophe and sequestration of free tubulin heterodimers. Stathmin expression is a feature of proliferating cells, and it is overexpressed in many cancers, including hematopoietic malignancies. In contrast to its roles in proliferating cells, considerably less is known of Stathmin 1 in quiescent cells. Notably, Stathmin 1 is highly expressed in hematopoietic stem and progenitor cells (HSPCs), and herein we found that loss of Stathmin 1 is associated with altered microtubule architecture and markedly impaired HSPC function. Transcriptomic studies suggested alterations in oxidative phosphorylation in Stmn1-/- HSPCs, and further mechanistic studies revealed defective mitochondrial structure and function in the absence of Stathmin 1 with increased ROS production. Microtubules associate with mitochondria and lysosomes to facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stathmin 1-deficient HSPCs. Finally, stimulation of autophagy improved the colony forming ability of Stmn1-/- HSPCs. Together, these data identify a novel, non-proliferative role for Stathmin 1 in the regulation of HSPC mitochondrial quality control and cellular function.