Hematopoietic transplantation can rescue neurological and cardiac deficits in a mouse model of Friedreich's ataxia (FA) — not by replacing diseased neurons or cardiomyocytes directly, but by delivering functional mitochondria to those cells through donor-derived myeloid cells, according to a study published August 15 in Nature Communications. The finding positions bone marrow transplantation as a potential mitochondrial delivery platform for inherited metabolic diseases affecting cell types that cannot themselves be transplanted.
The work, led by Natalia Gomez-Ospina at Stanford University's Department of Pediatrics and Stanford Institute for Stem Cell and Regenerative Medicine, addresses a core limitation of existing FA therapies: none directly correct the underlying bioenergetic defect across neurons and cardiomyocytes, the cell populations responsible for the disease's progressive neurological decline and cardiomyopathy.
FA is caused by frataxin deficiency, which impairs iron-sulfur cluster assembly and mitochondrial oxidative phosphorylation (OXPHOS). Using frataxin-deficient mice, the researchers found that hematopoietic transplantation improved survival, locomotion, strength, coordination, and cardiac function in both male and female animals. Recipient tissues showed increased expression of OXPHOS and ATP synthesis genes alongside elevated mitochondrial protein abundance, consistent with functional mitochondrial rescue rather than immune reconstitution alone.
Mechanistic experiments traced the rescue effect to mitochondrial transfer from donor-derived microglia and macrophages to host CNS and cardiac cells. In frataxin-deficient cells cultured in vitro, donor myeloid cells rescued respiratory capacity, while preventing direct contact between donor and recipient cells abolished the effect, indicating that rescue requires cell-cell contact rather than diffusible secreted factors. Frataxin-deficient recipient cells also showed enhanced mitochondrial uptake, consistent with metabolic stress increasing their acquisition of healthy organelles.