Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.

Mitochondrial respiration generates both energy (ATP) and reactive oxygen species (ROS). Insufficient energy and increased ROS from respiratory chain dysfunction may be central to the pathophysiology of neurodegenerative diseases and aging. We established a screening platform using CRISPR and fluorescent-cell sorting to compare the impact of decreasing respiratory chain proteins on ROS and ATP levels. The results provide the first systems-level analysis of how ROS and ATP are differentially regulated, and identify genes and respiratory chain complexes that can manipulate each independently. These findings advance our understanding of the relative contributions of ATP and ROS to disease pathophysiology, and guide the development of therapies to preserve energy while minimizing ROS.