Amino acid starvation has opposite effects on mitochondrial and cytosolic protein synthesis
Open accessAbstract
Amino acids are essential for cell growth and proliferation for they can serve as precursors of protein synthesis, be remodelled for nucleotide and fat biosynthesis, or be burnt as fuel. Mitochondria are energy producing organelles that additionally play a central role in amino acid homeostasis. One might expect mitochondrial metabolism to be geared towards the production and preservation of amino acids when cells are deprived of an exogenous supply. On the contrary, we find that human cells respond to amino acid starvation by upregulating the amino acid-consuming processes of respiration, protein synthesis, and amino acid catabolism in the mitochondria. The increased utilization of these nutrients in the organelle is not driven primarily by energy demand, as it occurs when glucose is plentiful. Instead it is proposed that the changes in the mitochondrial metabolism complement the repression of cytosolic protein synthesis to restrict cell growth and proliferation when amino acids are limiting. Therefore, stimulating mitochondrial function might offer a means of inhibiting nutrient-demanding anabolism that drives cellular proliferation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Amino acid starvation led to an inhibition of mTORC1 and a decrease in cytosolic protein synthesis, whereas there was an increase in active AMPK, mitochondria density, mitochondrial translation and function in human embryonic kidney cells.
“The authors found that amino acid starvation led to an inhibition of mTORC1 and a decrease in cytosolic protein synthesis, whereas there was an increase in active AMPK, mitochondria density (i.e., increased citrate synthase activity), mitochondrial translation and function.”
From Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities (2021) · cites this paper as Johnson et al., 2014
The Discussion and Results support inhibited TORC1 and cytosolic protein synthesis, increased active AMPK, and increased mitochondrial translation and respiration in human embryonic kidney cells. But the Discussion says that increased citrate synthase activity did not indicate increased mitochondrial mass; it reports no overall increase in mitochondrial biogenesis. The claimed increase in mitochondrial density is therefore not supported. (LLM, conf=0.93)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602 · see citing works
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181 · see citing works
Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139 · see citing works
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · see citing works
Mitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479 · see citing works
On Respiratory Impairment in Cancer Cells
Warburg, O. H. (1956) · Science · doi:10.1126/science.124.3215.269 · Cited by 3,472 · see citing works
Srere, P. A. (1969) · Methods in Enzymology · doi:10.1016/0076-6879(69)13005-0 · Cited by 2,005 · see citing works
During autophagy mitochondria elongate, are spared from degradation and sustain cell viability
Gomes, L. C., Benedetto, G. D., & Scorrano, L. (2011) · Nature Cell Biology · doi:10.1038/ncb2220 · Cited by 1,735 · see citing works
mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex
Cunningham, J. T., Rodgers, J. T., Arlow, D. H., Vazquez, F., Mootha, V. K., & Puigserver, P. (2007) · Nature · doi:10.1038/nature06322 · Cited by 1,488 · see citing works
Hara, K., Yonezawa, K., Weng, Q.-P., Kozlowski, M. T., BELHAM, C. M., & Avruch, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14484 · Cited by 1,370 · see citing works
Schulz, T. J., Zarse, K., Voigt, A., Urban, N., Birringer, M., & Ristow, M. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.08.011 · Cited by 1,209 · see citing works
Rambold, A. S., Kostelecky, B., Elia, N., & Lippincott‐Schwartz, J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1107402108 · Cited by 1,144 · see citing works
RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H., & Sabatini, D. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1432 · Cited by 1,130 · see citing works
Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span
Selman, C., Tullet, J. M. A., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., et al. (2009) · Science · doi:10.1126/science.1177221 · Cited by 1,120 · see citing works
Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration
Lin, S.-J., Kaeberlein, M., Andalis, A. A., Sturtz, L. A., Defossez, P.-A., Culotta, V. C., Fink, G. R., & Guarente, L. (2002) · Nature · doi:10.1038/nature00829 · Cited by 1,057 · see citing works
Mitochondrial transcription factor A regulates mtDNA copy number in mammals
Ekstrand, M. I. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh109 · Cited by 919 · see citing works
Energy Substrate Modulates Mitochondrial Structure and Oxidative Capacity in Cancer Cells
Rossignol, R., Gilkerson, R., Aggeler, R., Yamagata, K., Remington, S., & Capaldi, R. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1101 · Cited by 865 · see citing works
Transcriptional integration of mitochondrial biogenesis
Scarpulla, R. C., Vega, R. B., & Kelly, D. P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.06.006 · Cited by 798 · see citing works
Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans
Civitarese, A. E., Carling, S., Heilbronn, L. K., Hulver, M. H., Ukropcova, B., Deutsch, W. A., Smith, S. R., & Ravussin, E. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040076 · Cited by 790 · see citing works
Bentzinger, C. F., Romanino, K., Cloëtta, D., Lin, S., Mascarenhas, J. B., Oliveri, F., Xia, J., Casanova, E., Costa, C. F., Brink, M., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.10.002 · Cited by 640 · see citing works
Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase
Shima, H., Pende, M., Chen, Y., Fumagalli, S., THOMAS, G. V., & Kozma, S. C. (1998) · The EMBO Journal · doi:10.1093/emboj/17.22.6649 · Cited by 636 · see citing works
Schieke, S. M., Phillips, D., McCoy, J. P., Aponte, A. M., Shen, R.-F., Balaban, R. S., & Finkel, T. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603536200 · Cited by 623 · see citing works
4E-BP Extends Lifespan upon Dietary Restriction by Enhancing Mitochondrial Activity in Drosophila
Zid, B. M., Rogers, A. N., Katewa, S. D., Vargas, M. A., Kolipinski, M., Lu, T. A., Benzer, S., & Kapahi, P. (2009) · Cell · doi:10.1016/j.cell.2009.07.034 · Cited by 541 · see citing works
Mitochondria—A Nexus for Aging, Calorie Restriction, and Sirtuins?
Guarente, L. (2008) · Cell · doi:10.1016/j.cell.2008.01.007 · Cited by 513 · see citing works
Adipose-Specific Knockout of raptor Results in Lean Mice with Enhanced Mitochondrial Respiration
Polak, P., Cybulski, N., Feige, J. N., Auwerx, J., Rüegg, M. A., & Hall, M. N. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.09.003 · Cited by 480 · see citing works
Bonawitz, N. D., Chatenay-Lapointe, M., Pan, Y., & Shadel, G. S. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.02.009 · Cited by 422 · see citing works
Amino acid availability regulates p70 S6 kinase and multiple translation factors
Wang, X., Campbell, L., Miller, C. M., & Proud, C. G. (1998) · Biochemical Journal · doi:10.1042/bj3340261 · Cited by 338 · see citing works
Mitochondrial myopathy induces a starvation-like response
Tyynismaa, H., Carroll, C. J., Raimundo, N., Ahola-Erkkilä, S., Wenz, T., Ruhanen, H., Guse, K., Hemminki, A., Peltola-Mjøsund, K. E., Tulkki, V., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq310 · Cited by 300 · see citing works
Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis
He, J.-Y., Cooper, H. M., Reyes, A., Re, M. D., Sembongi, H., Litwin, T., Gao, J., Neuman, K., Fearnley, I., Spinazzola, A., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks266 · Cited by 220 · see citing works
Self-citationHuman Mitochondrial Transcription Revisited
Litonin, D., Sologub, M., Shi, Y., Savkina, M. V., Anikin, M., Falkenberg, M., Gustafsson, C. M., & Temiakov, D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.c110.128918 · Cited by 212 · see citing works
[18] In vivo labeling and analysis of human mitochondrial translation products
Chomyn, A. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)64020-8 · Cited by 207 · see citing works
Hämäläinen, R. H., Manninen, T., Koivumäki, H., Kislin, M., Otonkoski, T., & Suomalainen, A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311660110 · Cited by 201 · see citing works
TEFM (c17orf42) is necessary for transcription of human mtDNA
Minczuk, M. A., He, J., Duch, A. M., Ettema, T. J. G., Chlebowski, A., Dzionek, K., Nijtmans, L. G. J., Huynen, M. A., & Holt, I. J. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkq1224 · Cited by 178 · see citing works
Self-citationMitochondrial biogenesis and turnover
Diaz, F., & Moraes, C. T. (2008) · Cell Calcium · doi:10.1016/j.ceca.2007.12.004 · Cited by 151 · see citing works
Analysis of overrepresented motifs in human core promoters reveals dual regulatory roles of YY1Preprint
Xi, H. S., Yu, Y., Fu, Y., Foley, J., Halees, A. S., & Weng, Z. (2007) · Genome Research · doi:10.1101/gr.5754707 · Cited by 115 · see citing works
The peroxin Pex14p is involved in LC3-dependent degradation of mammalian peroxisomes.
Hara-Kuge, S., & Fujiki, Y. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.09.015 · Cited by 108 · see citing works
Core human mitochondrial transcription apparatus is a regulated two-component system in vitro
Shutt, T. E., Lodeiro, M. F., Cotney, J. L., Cameron, C. E., & Shadel, G. S. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910581107 · Cited by 96 · see citing works
He, J., Cooper, H. M., Reyes, A., Re, M. D., Kazak, L., Wood, S. R., Mao, C. C., Fearnley, I. M., Walker, J. E., & Holt, I. J. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks257 · Cited by 89 · see citing works
Self-citationKoc, E. C., Çimen, H., Kumcuoglu, B., et al. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00183 · Cited by 85 · see citing works
Bandhakavi, S., Xie, H., O’Callaghan, B. L., Sakurai, H., Kim, D., & Griffin, T. J. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001598 · Cited by 42 · see citing works
Contractile activity-induced mitochondrial biogenesis and mTORC1
Carter, H. N., & Hood, D. A. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00156.2012 · Cited by 40 · see citing works
Interaction of mitochondrial elongation factor Tu with aminoacyl-tRNAs
Hunter, S. E., & Spremulli, L. L. (2004) · Mitochondrion · doi:10.1016/j.mito.2004.04.003 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mesquita, P. H. C., Vann, C. G., Phillips, S. M., McKendry, J., Young, K. C., Kavazis, A. N., & Roberts, M. D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.725866 · Cited by 62 · see citing works
- Authors
- Johnson, M. A., Vidoni, S., Durigon, R., Pearce, S. F., Rorbach, J., He, J., Brea-Calvo, G., Minczuk, M., Reyes, A., Holt, I. J., & Spinazzola, A.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- National Institute for Medical Research (GB)
- Corresponding author
- Spinazzola, Antonella
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-04-09
- Volume
- 9
- Issue
- 4
- Pages
- e93597
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3981720
- OpenAlex
- W2034929921
- Cited by
- 63
- References
- 45
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 4 · 2015: 5 · 2014: 2
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- European Commission (255578)
- Medical Research Council (MC_PC_13029/1)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- amino acid starvation, mitochondrial translation, amino acid homeostasis, mitochondrial metabolism, amino acid catabolism, cellular respiration, cell proliferation, cell growth, human cells
- MeSH terms
- Amino Acids, Cytosol, Humans, Mitochondria, RNA, Messenger, Protein Biosynthesis, Cell Respiration, Mitochondrial Proteins, Membrane Potential, Mitochondrial, HEK293 Cells, Mitochondrial Turnover
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
