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

Abstract

Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics. Stathmin 1 expression is a feature of proliferating cells, and it is overexpressed in many cancers, including leukemias. In contrast to its roles in proliferating cells, considerably less is known of stathmin 1 in quiescent cells. Importantly, stathmin 1 is highly expressed in hematopoietic stem and progenitor cells (HSPCs), and herein we found that stathmin 1 loss is associated with altered microtubule architecture and markedly impaired HSPC function. Transcriptomic studies suggested metabolic differences in Stmn1 −/− HSPCs, and further mechanistic studies revealed defective mitochondrial structure and function. Microtubules facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stmn1 −/− HSPCs. Finally, stimulation of autophagy improved Stmn1 −/− HSPC colony-forming ability. Together, these data identify a non-proliferative role for stathmin 1 in the regulation of HSPC mitochondrial quality control and cellular function.