Mitochondria are the primary source of the H ₂O ₂ signal for glucocorticoid-induced apoptosis of lymphoma cells

Glucocorticoids are a class of steroid hormones commonly used for the treatment of hematological malignancies due to their ability to induce apoptosis in lymphoid cells. An understanding of the critical steps in glucocorticoid-induced apoptosis is required to identify sources of drug resistance. Previously, we found that an increase in hydrogen peroxide is a necessary signal for glucocorticoid-induced apoptosis. In the current study, we found that mitochondria are the source of the signal. Glucocorticoid treatment inhibited Complex I and Complex III of the electron transport chain (ETC). Mitochondrial matrix reactive oxygen species (ROS) increased concomitantly with the oxidation of the mitochondrial glutathione pool. Treatment with Tiron, a superoxide scavenger, inhibited the signal. This suggests that the hydrogen peroxide signal originates as superoxide from the mitochondria and is metabolized to hydrogen peroxide. An inability to generate mitochondrial oxidants in response to glucocorticoids could cause drug resistance.