Targeting mitochondria mitigates chemotherapy-induced bone marrow dysfunction

Chemotherapy has revolutionized cancer treatment but its long-term impact on healthy tissues, particularly the rapidly dividing hematopoietic system, remains a significant concern. We show that the chemotherapeutic agent 5-fluorouracil (5-FU) causes significant long-term defects of the hematopoietic system that mimics ageing, including myeloid lineage skewing and hematopoietic stem cell (HSC) dysfunction. Importantly, chemotherapy exposed HSCs remain in an inflammatory state coupled with mitochondrial dysfunction, both of which are implicated in ageing and MDS development. Remarkably, five days of MitoQ treatment fully reversed 5-FU-induced myeloid skewing and caused significant recovery of HSC transcriptome and function in a stable manner. Thus, our results demonstrate that repeated chemotherapy induces long-term bone marrow dysfunction driven by metabolically unfit HSCs that can be pharmacologically rescued. This work opens up novel avenues to explore supportive treatment for patients undergoing any type of myelo-ablative chemotherapy. HighlightsO_LICommonly used chemotherapy drugs cause stable lineage-specific cytopenias despite recovery of total blood counts. C_LIO_LI5-FU-induced hematopoietic dysfunction phenocopies premature hematopoietic ageing. C_LIO_LIChemotherapy-induced changes stem from HSCs that are self-renewal competent but differentiation incompetent. C_LIO_LIMitochondrial-targeted treatment rescues 5-FU-induced myeloid bias through correction of HSC transcriptome and function. C_LI