Accumulation of mitochondrial ROS drives reductive glutamine metabolism

Hypoxia, mitochondrial defect or extracellular matrix detachment induces reductive glutamine metabolism that can produce citrate by carboxylating the glutamine-derived ketoglutarate (-KG). Reductive carboxylation is required for maintaining redox homeostasis, lipogenesis and cancer cell growth. However, the fundamental mechanism(s) of how reductive glutamine metabolism may be controlled is not fully understood. This study here demonstrates that mitochondrial-derived reactive oxygen species (ROS) positively drives reductive carboxylation. Knockout of fatty acid synthase (FASN) causes increased mitochondrial ROS and significant reductive glutamine metabolism. Mitochondrial ROS accumulation is identified as a shared feature in cells that utilize reductive metabolism. Moreover, ROS scavenger could inhibit reductive carboxylation by decreasing ROS level in mitochondria. By contrast, ROS inducers activate reductive carboxylation via increasing mitochondrial ROS. Mitochondrial ROS level determines the degree of reductive carboxylation with a positive correlation. The results presented here not only reveal a fundamental mechanism of how reductive carboxylation is controlled, but also elucidate a critical role of ROS in reprogramming metabolism.