An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis
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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.
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The availability of NAD+ as an electron acceptor enables aspartate synthesis through aspartate aminotransferase and rescues the proliferation of cultured cells with dysfunctions or inhibition of the electron transport system.
“The availability of NAD+ as an electron acceptor enables aspartate synthesis through aspartate aminotransferase and rescues the proliferation of cultured cells with dysfunctions or inhibition of the electron transport system [16,17].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [16]
The Results and Discussion sections report that pyruvate restores aspartate synthesis through GOT1, an aspartate aminotransferase, and rescues proliferation in cultured cells with inhibited or defective ETC activity. The proposed role of regenerated NAD+ in driving this pathway through MDH1 is described as a model, however; the claim presents NAD+ availability as an established cause. Page numbers are unavailable in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMitochondrial respiration remains important in proliferating cells, allowing production of biosynthetic precursors and electron acceptors that enable aspartate synthesis.
“Despite the prevalence of glycolysis, mitochondrial respiration remains important in proliferating cells, allowing the production of biosynthetic precursors and the generation of electron acceptors that enable aspartate synthesis, for example [9,16,17].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [16]
Genetic or epigenetic silencing of ASS1 provides an advantage to tumor cells by allowing them to preserve cellular aspartate, a poorly transported nutrient that can be a critical output of the TCA cycle to support de novo nucleotide synthesis and cell proliferation.
“Genetic or epigenetic silencing of ASS1 expression provides an advantage to tumor cells by allowing them to preserve cellular aspartate (Rabinovich et al., 2015), a poorly transported nutrient that can be a critical output of the TCA cycle to support de novo nucleotide synthesis and cell proliferation (Birsoy et al., 2015; Sullivan et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Birsoy et al., 2015
Respiration serves an anabolic role for proliferating cells by regenerating NAD+ from NADH.
“Instead, respiration serves an alternative anabolic role for proliferating cells by regenerating the oxidized form of nicotinamide adenine dinucleotide (NAD+) from the reduced form (NADH) (Birsoy et al., 2015; Sullivan et al., 2015; Titov et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Birsoy et al., 2015
Mitochondrial ATP production appears dispensable for many proliferating cells.
“However, mitochondrial ATP production appears dispensable for many proliferating cells (Birsoy et al., 2015; Sullivan et al., 2015; Titov et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Birsoy et al., 2015
Glutamate is converted into aspartate in cells with a dysfunctional electron transport chain to promote proliferation, allowing tumor cells to adapt rapidly to available substrates in their TME niche.
“For example, glutamate is converted into aspartate in cells with a dysfunctional electron transport chain to promote proliferation, allowing tumor cells to adapt rapidly to the substrates available in their TME niche [224, 225].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [224]
Upon ETC dysfunction, the cytosolic steps of the malate-aspartate shuttle can reverse to produce cytosolic aspartate.
“Upon ETC dysfunction, the cytosolic steps of the malate–aspartate shuttle can reverse to produce, rather than consume, cytosolic aspartate (42, 43).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [42]
Aspartate biosynthesis is critically dependent on a cell's ability to conduct oxidative phosphorylation.
“In fact, aspartate biosynthesis has recently been shown to be critically dependent upon a cell’s ability to conduct oxidative phosphorylation (Birsoy et al., 2015; Sullivan et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Birsoy et al., 2015
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- Authors
- Birsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Sabatini, David M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 162
- Issue
- 3
- Pages
- 540-551
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4522279
- OpenAlex
- W1932780354
- Cited by
- 1,388
- References
- 61
- Citations by year
- 2026: 124 · 2025: 139 · 2024: 145 · 2023: 147 · 2022: 153 · 2021: 138 · 2020: 161 · 2019: 106 · 2018: 100 · 2017: 87 · 2016: 71 · 2015: 14 · 2014: 1
- FWCI
- 30.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (CA103866, R01CA103866, F31CA189437)
- National Institute of General Medical Sciences (T32GM007753, T32GM007287)
- National Institute of Allergy and Infectious Diseases (R37AI047389, AI047389, R01AI047389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mitochondrial electron transport chain, cell proliferation, aspartate synthesis, GOT1, cytosolic aspartate aminotransferase, phenformin, mitochondrial complex I inhibition, pyruvate, CRISPR screen
- MeSH terms
- Aspartic Acid, DNA, Mitochondrial, Electron Transport, Humans, Mitochondria, Mutation, Phenformin, Jurkat Cells, Pyruvic Acid, Aspartate Aminotransferase, Cytoplasmic, Cell Proliferation
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