An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis

By Kıvanç Birsoy, Tim Wang, Walter W. Chen, Elizaveta Freinkman, Monther Abu-Remaileh, David M. Sabatini. Cell, 2015

1,285 citations recorded by the source corpus.

Summary The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation.

Subfields: Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/eb3b1b6daf488650cec3d6a6c42faf3d07d1f89d

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In Clinical Biochemistry

1. M. V. Vander Heiden
2. Joshua D. Rabinowitz

In Molecular Biology

1. Guido Kroemer
2. L. Galluzzi
3. M. V. Vander Heiden
4. Ralph J. Deberardinis
5. D. Y. Gui
6. Alba Luengo
7. E. White
8. Joshua D. Rabinowitz

Citations in the corpus

• Mitochondria and Cancer (2016, background): “CRISPR-based screening identified GOT1 as required for cell growth in the presence of pharmacological ETC inhibition (Birsoy et al., 2015).”
• Mitochondrial metabolism and cancer (2017, background): “Although in vitro, under optimal growth conditions (which differ significantly from those encountered in the tumor microenvironment in vivo), cancer cells can obtain sufficient ATP from glycolysis, mitochondria are required for proliferation unless supraphysiological amounts of uridine and pyruvate ”
• Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “PFAS: phosphoribosylformylglycinamidine synthase ETC: electron transport chain certain nonessential amino acids.”
• Copper induces cell death by targeting lipoylated TCA cycle proteins (2022, methodology): “These observations were validated by an independent knock-out screen focusing on 3,000 metabolic enzymes (27) (table S2 and Fig.”
• Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells (2015, background): “Notably, aspartate is inefficiently transported into most mammalian cells (Birsoy et al., 2015, this issue), with supra-physiological concentrations required to restore growth in electron acceptor deficient cells.”
• Understanding the intersections between metabolism and cancer biology (2017, positive): “Regenerating NAD+ via orthogonal pathways can also increase cell proliferation when respiration is impaired (Birsoy et al., 2015; Sullivan et al., 2015; Titov et al., 2016), and disposal of excess electrons can limit proliferation in prokaryotic systems (Dietrich et al.”
• Targeting Metabolism for Cancer Therapy (2017, background): “Proliferating cells often require a high NAD+/NADH ratio to support anabolic reactions, and in some contexts the NAD+/NADH ratio directly correlates with proliferation rate (Gui et al., 2016).”