MITOCHONDRIAL ROS AND LYTIC PROGRAMMED CELL DEATH IN ACUTE INFLAMMATION.

Abstract

Redox signaling through mitochondrial reactive oxygen species (ROS) has a key role in several mechanisms of regulated cell death, necroptosis, ferroptosis, pyroptosis, and apoptosis, thereby decisively contributing to inflammatory disorders. The role of mitochondrial ROS in apoptosis has been extensively addressed, but their involvement in necrotic-like regulated cell death has just started to be elucidated, providing novel insights into the pathophysiology of acute inflammation. Mitochondrial ROS trigger positive feedback loops leading to lytic regulated cell death in conjunction with the necrosome, the inflammasome, glutathione depletion, and glutathione peroxidase 4 deficiency. p53 together with mitochondrial ROS drive necroptosis in acute inflammation through downregulation of sulfiredoxin and peroxiredoxin 3. Mitochondrial hydroorotate dehydrogenase is a key redox system in the regulation of ferroptosis. In addition, a non-canonical pathway, which generates mitochondrial ROS through the Ragulator-Rag complex and acts via mTORC1 to promote gasdermin D oligomerization, triggers pyroptosis. The precise mechanism of membrane rupture in ferroptosis and the contribution of mitochondrial ROS to ferroptosis in inflammatory disorders are still unclear, which will need further research. Mitochondrial antioxidants may provide promising therapeutic approaches towards acute inflammatory disorders. However, establishing doses and windows of action will be required to optimize their therapeutic potential, and to avoid potential adverse side effects linked to blockade of beneficial mitochondrial ROS adaptive signaling.