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.

Automated summary

Preconditioning with low concentrations of inhaled carbon monoxide (CO) offers protection against hypoxic and ischemic insults in the brain and heart. This study suggests that the activation of mitochondrial-derived vesicles (MDVs) may be the mechanism underlying the protective effect of CO preconditioning. By inducing mild oxidative stress and promoting the production of MDVs, CO preconditioning prevents cell death in oligodendrocyte precursor cells (OPCs) and Chinese hamster ovary (CHO) cells under stressful conditions. Inhibition of lysosomal activity disrupts MDV degradation and mitochondrial quality control, reducing the protective effect of CO preconditioning.