Abstract
Oxygen controls most metazoan metabolism, yet in mammals, tissue O2 levels vary widely. While extensive research has explored cellular responses to hypoxia, understanding how cells respond to physiologically high O2 levels remains uncertain. To address this problem, we investigated respiratory epithelia as their contact with air exposes them to some of the highest O2 levels in the body. We asked how the O2 level in air controls differentiation of airway basal stem cells into the ciliated epithelial cells essential for clearing airborne pathogens from the lung. Through a metabolomics screen and 13C tracing on primary cultures of human airway basal cells, we found that the O2 level in air directs ciliated cell differentiation by increasing mitochondrial citrate export. Unexpectedly, disrupting mitochondrial citrate export elicited hypoxia transcriptional responses independently of HIF1α stabilization and at O2 levels that would be hyperoxic for most tissues. These findings identify mitochondrial citrate export as a cellular mechanism for responding to physiologically high O2 levels.