Significance: Redox signaling through mitochondrial reactive oxygen species (mtROS) has a key role in several mechanisms of regulated cell death (RCD), necroptosis, ferroptosis, pyroptosis, and apoptosis, thereby decisively contributing to inflammatory disorders. The role of mtROS in apoptosis has been extensively addressed, but their involvement in necrotic-like RCD has just started being elucidated, providing novel insights into the pathophysiology of acute inflammation. Recent Advances: p53 together with mtROS 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 noncanonical pathway, which generates mtROS through the Ragulator-Rag complex and acts via mTORC1 to promote gasdermin D oligomerization, triggers pyroptosis. Critical Issues: mtROS trigger positive feedback loops leading to lytic RCD in conjunction with the necrosome, the inflammasome, glutathione depletion, and glutathione peroxidase 4 deficiency. Future Directions: The precise mechanism of membrane rupture in ferroptosis and the contribution of mtROS to ferroptosis in inflammatory disorders are still unclear, which will need further research. Mitochondrial antioxidants may provide promising therapeutic approaches toward 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 the blockade of beneficial mtROS adaptive signaling. Antioxid. Redox Signal. 39, 708-727.
Keywords: ferroptosis; hydrogen peroxide; mitochondria; necroptosis; pyroptosis; superoxide anion.