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Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells
Open accessAbstract
Mitochondrial respiration is important for cell proliferation; however, the specific metabolic requirements fulfilled by respiration to support proliferation have not been defined. Here, we show that a major role of respiration in proliferating cells is to provide electron acceptors for aspartate synthesis. This finding is consistent with the observation that cells lacking a functional respiratory chain are auxotrophic for pyruvate, which serves as an exogenous electron acceptor. Further, the pyruvate requirement can be fulfilled with an alternative electron acceptor, alpha-ketobutyrate, which provides cells neither carbon nor ATP. Alpha-ketobutyrate restores proliferation when respiration is inhibited, suggesting that an alternative electron acceptor can substitute for respiration to support proliferation. We find that electron acceptors are limiting for producing aspartate, and supplying aspartate enables proliferation of respiration deficient cells in the absence of exogenous electron acceptors. Together, these data argue a major function of respiration in proliferating cells is to support aspartate synthesis.
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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 [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 [17]
The cited source says what the claim attributes to it.
In the citing paper
“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 [17]
In the citing paper
“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 Sullivan et al., 2015
In the citing paper
“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 Sullivan et al., 2015
In the citing paper
“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 Sullivan et al., 2015
In the citing paper
“For example, eliminating environmental serine, limiting aspartate synthesis via mitochondrial inhibition, and ablating the mitochondrial folate pathway impairs purine biosynthesis (Ducker et al., 2016; Labuschagne et al., 2014; Sullivan et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Sullivan et al., 2015
In the citing paper
“Additionally, glutamine-derived aspartate plays a crucial role in hypoxic environments or environments with electron transport chain (ETC) impairment28.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [28]
In the citing paper
“Aspartate, which is derived from the transamination of glutamine to form glutamate, participates in pyrimidine and purine biosynthesis28.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [28]
In the citing paper
“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 [43]
In the citing paper
“Aspartate is used to support protein and nucleotide synthesis in proliferating cells and sustains proliferation in the face of OXPHOS impairment (214).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [214]
In the citing paper
“Time-restricted feeding restores both cycling of metabolic regulators such as cAMP response element-binding protein, mTOR and AMPK, and circadian clock gene expression (214).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [214]
In the citing paper
“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 Sullivan et al., 2015
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Metadata
- Authors
- Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Whitehead Institute for Biomedical Research (US)
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 162
- Issue
- 3
- Pages
- 552-563
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4522278
- OpenAlex
- W1553978925
- Cited by
- 1,173
- References
- 55
- Citations by year
- 2026: 106 · 2025: 95 · 2024: 97 · 2023: 120 · 2022: 151 · 2021: 129 · 2020: 128 · 2019: 90 · 2018: 98 · 2017: 75 · 2016: 71 · 2015: 11
- FWCI
- 28.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Public Health Service (GG006413)
- National Cancer Institute (P30CA1405141, R01CA168653, P30CA014051)
- National Institute of General Medical Sciences (T32GM007753, T32GM007287)
- 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 › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- mitochondrial respiration, aspartate biosynthesis, cell proliferation, electron acceptors, pyruvate, alpha-ketobutyrate, respiratory chain deficiency, auxotrophy, alternative electron acceptors
- MeSH terms
- Adenosine Triphosphate, Aspartic Acid, Butyrates, Electrons, Humans, Mitochondria, Nucleotides, Cell Respiration, Pyruvic Acid, Cell Line, Tumor, Cell Proliferation
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