Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem cells

• DOI: 10.1101/2025.03.10.642434
• Publication Date: 2025-03-13T09:30:16Z
• Authors: Luana Chiquetto; Meg Schuetz; Qian Dong; Mia Warmka; Liana Valin; Ashley Jones; Patrick Hunt; Copper Petermeier; Jie Wang; Nate Roundy; Zev J. Greenberg; Wei Yang; Christine R. Zhang; Grant A. Challen; Cliff J. Luke; Robert A. J. Signer; Wandy L. Beatty; Stephen Sykes; Weikai Li; David J. Kast; Laura G. Schuettpelz

AbstractStathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics via promotion of microtubule catastrophe and sequestration of free tubulin heterodimers. Stathmin 1 is highly expressed in hematopoietic stem cells (HSCs), and overexpressed in leukemic cells, however its role in HSCs is not known. Herein, we found that loss of Stathmin 1 is associated with altered microtubule architecture in HSCs, and markedly impaired HSC function. Transcriptomic studies suggested alterations in oxidative phosphorylation inStmn1-/-HSCs, 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 HSCs. Finally, stimulation of autophagy improved the colony forming ability ofStmn1-/-hematopoietic stem and progenitor cells. Together, our data identify Stathmin 1 as a novel regulator of mitophagy and mitochondrial health in HSCs.Key PointsThe microtubule regulating protein Stathmin 1 is highly expressed in HSPCs and promotes normal microtubule architecture.Loss of Stathmin 1 in HSPCs leads to impaired autophagy with abnormal mitochondrial morphology, decreased respiratory capacity, and impaired cellular function.