Genetic Screen for Cell Fitness in High or Low Oxygen Highlights Mitochondrial and Lipid Metabolism

Cell. 2020 Apr 30;181(3):716-727.e11. doi: 10.1016/j.cell.2020.03.029. Epub 2020 Apr 6.


Human cells are able to sense and adapt to variations in oxygen levels. Historically, much research in this field has focused on hypoxia-inducible factor (HIF) signaling and reactive oxygen species (ROS). Here, we perform genome-wide CRISPR growth screens at 21%, 5%, and 1% oxygen to systematically identify gene knockouts with relative fitness defects in high oxygen (213 genes) or low oxygen (109 genes), most without known connection to HIF or ROS. Knockouts of many mitochondrial pathways thought to be essential, including complex I and enzymes in Fe-S biosynthesis, grow relatively well at low oxygen and thus are buffered by hypoxia. In contrast, in certain cell types, knockout of lipid biosynthetic and peroxisomal genes causes fitness defects only in low oxygen. Our resource nominates genetic diseases whose severity may be modulated by oxygen and links hundreds of genes to oxygen homeostasis.

Keywords: CoQ biosynthesis; FASII; MPC; TMEM189; hypoxia; iron-sulfur clusters; membrane fluidity; plasmalogens; pyruvate dehydrogenase; type II fatty acid synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Hypoxia
  • Genetic Testing / methods
  • Genome-Wide Association Study / methods
  • HEK293 Cells
  • Humans
  • Hypoxia / metabolism
  • K562 Cells
  • Lipid Metabolism / genetics*
  • Lipid Metabolism / physiology
  • Lipids / genetics
  • Lipids / physiology
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Oxygen / metabolism*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / physiology
  • Transcriptome / genetics*


  • Lipids
  • Reactive Oxygen Species
  • Oxygen