Myeloid Cell Replacement Therapy Improves Function in Friedreich Ataxia Mice by Intercellular Mitochondrial Transfer

Friedreich's ataxia (FA) is a mitochondrial disease caused by frataxin deficiency, leading to neurodegeneration and cardiomyopathy. Currently, there are no effective therapies for FA. Our study investigated the potential of myeloid cell replacement using bone marrow-derived cells in the YG8-800 mouse model. Combining Busulfan myeloablation, Colony-stimulating factor 1 receptor inhibition, and bone marrow transplantation, we achieved almost complete microglia and tissue macrophage replacement. This replacement facilitated mitochondrial transfer to various CNS cells, enhancing ATP synthesis and oxidative phosphorylation and improving the mice's growth and neurobehavioral performance. Similarly, replacing macrophages restored function and increased mitochondrial activity in the heart. In vitro studies showed that transferring intact mitochondria partially restored respiratory capacity in FA cells, which had a higher uptake, suggesting a specific compensatory mechanism for mitochondrial acquisition. These findings suggest that myeloid cell replacement can promote metabolic recovery in FA through mitochondrial transfer and provide a new approach to treating FA and other mitochondrial disorders.