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Updated: Aug 14, 2025
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In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice
Published on: November 22, 2017
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OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis
Xiang Li1,2, Xiaojing Yue1, Hugo Sepulveda1
1Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.
Summary
O-GlcNAc transferase (OGT) regulates cell viability by suppressing proteasome activity, which maintains mitochondrial function and low mTOR signaling. OGT deficiency causes mitochondrial dysfunction via proteasome/mTOR pathway activation.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- O-GlcNAc transferase (OGT) is crucial for mammalian cell survival, yet its precise mechanisms remain unclear.
- OGT attaches O-linked N-acetylglucosamine (GlcNAc) to serine and threonine residues in nuclear and cytosolic proteins.
Purpose of the Study:
- To identify genes that, when depleted, rescue the proliferation defect caused by OGT deficiency.
- To elucidate the molecular mechanisms underlying OGT's essential role in cell viability.
Main Methods:
- Genome-wide CRISPR-Cas9 screening in mouse embryonic stem cells (mESCs).
- Phospho-proteomic screening to confirm mTOR pathway activation.
- Analysis of the proteasome/mTOR/mitochondrial axis.
Main Results:
- OGT deficiency leads to cell proliferation arrest due to mitochondrial dysfunction.
- This dysfunction is caused by hyperactivation of the mechanistic target of rapamycin (mTOR) pathway.
- OGT normally suppresses proteasome activity, maintaining low amino acid levels and mitochondrial fitness. OGT absence increases proteasome activity, raising amino acids, promoting mTOR activation, and increasing oxidative phosphorylation.
Conclusions:
- OGT maintains cellular homeostasis by regulating the proteasome/mTOR/mitochondrial axis, impacting amino acid levels and mitochondrial health.
- This regulatory mechanism is conserved in CD8+ T cells, suggesting broad biological relevance.
- Targeting OGT activity presents potential therapeutic strategies for diseases linked to this pathway.
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