Carbon monoxide preconditioning is mediated via activation of mitochondrial-derived vesicles

Preconditioning with inhalative carbon monoxide (CO) at low concentrations provides protection against hyp-oxic and ischemic insults in the brain and heart. The present study aims to test a hypothesis that activation of mitochondrial-derived vesicles (MDVs) is a mechanism underlying the protective effect of CO preconditioning. Here we show that CO preconditioning induced mild oxidative stress and activated massive production of MDVs. Short exposure to a low concentration of carbon monoxide-releasing molecule 2 (CORM-2), a donor of carbon monoxide, prevented oligodendrocyte precursor cells (OPCs) from subsequent death induced by high doses of CO, and protected Chinese hamster ovary (CHO) cells against oxygen-glucose deprivation (OGD)-induced cell death. Furthermore, inhibition of lysosomal activity prevented degradation of MDVs, abolished MDV-mediated mitochondrial quality control, and diminished the protective effect of CO preconditioning. Altogether, our data provide direct evidence suggesting that MDV-mediated mitochondrial quality control may have a novel role in CO preconditioning.