Abstract
Hematopoietic stem cells (HSCs) are sensitive to ionizing radiation (IR) damage, and its injury is the primary cause of bone marrow (BM) hematopoietic failure and even death after exposure to a certain dose of IR. However, the underlying mechanisms remain incompletely understood. Here we show that mitochondrial oxidative damage, which is characterized by mitochondrial reactive oxygen species overproduction, mitochondrial membrane potential reduction and mitochondrial permeability transition pore opening, is rapidly induced in both human and mouse HSCs and directly accelerates HSC apoptosis after IR exposure. Mechanistically, 5-lipoxygenase (5-LOX) is induced by IR exposure and contributes to IR-induced mitochondrial oxidative damage through inducing lipid peroxidation. Intriguingly, a natural antioxidant, caffeic acid (CA), can attenuate IR-induced HSC apoptosis through suppressing 5-LOX-mediated mitochondrial oxidative damage, thus protecting against BM hematopoietic failure after IR exposure. These findings uncover a critical role for mitochondria in IR-induced HSC injury and highlight the therapeutic potential of CA in BM hematopoietic failure induced by IR.