Cited by 226Cancer, Hypoxia, and MetabolismRedox biology and oxidative stressMitochondrial Function and Pathology

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

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Jain, Isha H., Calvo, Sarah E., Markhard, Andrew L., Skinner, Owen S., To, Tsz-Leung, Ast, Tslil, Mootha, Vamsi K.·2020·Cell

DOI 10.1016/j.cell.2020.03.029PMC PMC7293541

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Abstract

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.

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Authors: Jain, I. H., Calvo, S. E., Markhard, A. L., Skinner, O. S., To, T.-L., Ast, T., & Mootha, V. K.
Affiliations: Broad Institute (US)
Corresponding author: Mootha, Vamsi K.
ORCID: Jain, Isha H.
Calvo, Sarah E.
Skinner, Owen S.
To, Tsz-Leung
Ast, Tslil
Mootha, Vamsi K.
Venue: Cell
Publisher: Elsevier BV
Published: 2020-04
Volume: 181
Issue: 3
Pages: 716-727.e11
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2020.03.029
PMC: PMC7293541
OpenAlex: W3014660178
Semantic Scholar: f5cf6ffc17c0afcf964c1821338eea659750c183
Cited by: 224
References: 71
Citations by year: 2026: 30 · 2025: 42 · 2024: 33 · 2023: 37 · 2022: 30 · 2021: 37 · 2020: 14
FWCI: 10.09
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 394 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders: National Institutes of Health (1F32GM133047-01)
J. Willard and Alice S. Marriott Foundation
U.S. Department of Energy
Howard Hughes Medical Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords: oxygen homeostasis, hypoxia, cell fitness, genome-wide CRISPR screen, mitochondrial metabolism, lipid metabolism, complex I, peroxisomes, lipogenesis, hypoxia-inducible factor, reactive oxygen species
MeSH terms: Hypoxia, Genetic Testing, Humans, Lipids, Mitochondria, Oxygen, Signal Transduction, Cell Hypoxia, Reactive Oxygen Species, K562 Cells, Lipid Metabolism, Genome-Wide Association Study, HEK293 Cells, Transcriptome

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

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