Compared with controls (left), fewer stressed-out kidney cells commit suicide (red) in the absence of NADPH oxidase (right).
Compared with controls (left), fewer stressed-out kidney cells commit suicide (red) in the absence of NADPH oxidase (right).
Cells have to cope with different sources of stress. show how two potentially lethal kinds of cellular stress amplify each other.
Oxidative stress puts cells under pressure due to buildup of potentially damaging reactive oxygen species (ROS), whereas the accumulation of misshapen proteins in the endoplasmic reticulum (ER) can trigger ER stress, which cells try to alleviate through the unfolded protein response. Both kinds of stress can spur cell suicide and help drive several chronic diseases, including atherosclerosis and diabetes. Although researchers have long suspected a destructive synergy between oxidative and ER stress, the molecular connection between the two has remained elusive.
Li et al. teased out a link in stressed macrophages, which the researchers chose to study because they contribute to atherosclerosis. In these cells, ER stress induced ROS production through a pathway that included NADPH oxidase. To their surprise, the researchers found that activation of NADPH oxidase also revs up ER stress, indirectly boosting expression of a key apoptotic protein called CHOP. “There is this incredible tango between ER and oxidative stress that is integrated by NADPH oxidase,” says senior author Ira Tabas.
ER stress often kills macrophages. But Li et al. found that the death rate was much lower in cells lacking the major version of NADPH oxidase. The authors then tested the enzyme's effects in vivo by tracking another cell type that is vulnerable to ER and oxidative stress during disease—kidney cells. After injections of a compound that triggers ER stress, mice missing NADPH oxidase showed less apopotosis in kidney tubule cells than did control animals. However, NADPH oxidase is essential for fighting pathogens, so shutting it down could be risky. But drugs that merely reduce its activity to normal levels might ease both kinds of stress without lowering immune defenses.
