Mitoquinone restores platelet production in irradiation-induced thrombocytopenia

Abstract

Myelodysplastic syndromes (MDS) are hallmarked by cytopenia and dysplasia of hematopoietic cells, often accompanied by mitochondrial dysfunction and increases of reactive oxygen species (ROS) within affected cells. However, it is not known whether the increase in ROS production is an instigator or a byproduct of the disease. The present investigation shows that mice lacking immediate early responsive gene X-1 (IEX-1) exhibit lineage specific increases in ROS production and abnormal cytology upon radiation in blood cell types commonly identified in MDS. These affected cell lineages chiefly have the bone marrow as a primary site of differentiation and maturation, while cells with extramedullary differentiation and maturation like B- and T-cells remain unaffected. Increased ROS production is likely to contribute significantly to irradiation-induced thrombocytopenia in the absence of IEX-1 as demonstrated by effective reversal of the disorder after mitoquinone (MitoQ) treatment, a mitochondria-specific antioxidant. MitoQ reduced intracellular ROS production within megakaryocytes and platelets. It also normalized mitochondrial membrane potential and superoxide production in platelets in irradiated, IEX-1 deficient mice. The lineage-specific effects of mitochondrial ROS may help us understand the etiology of thrombocytopenia in association with MDS in a subgroup of the patients.

• Megakaryocytes
• Mitoquinone
• Reactive Oxygen Species
• Thrombocytopenia

Acknowledgements

We thank Dr. Michael P. Murphy for the generous gift of MitoQ used in this study.

Declaration of interest

The authors declare no conflict of interest.

H.R. designed and performed the research, analyzed data, and wrote the manuscript. Q.Z performed research. M.W. has designed and supervised research and wrote the manuscript. This work is supported by the National Institutes of Health Grants CA158756, AI089779, and DA028378 to M.X.W.