Evidence map›Paper›PMID 31133756›Full record

ArticleNature chemical biology2019

Mitochondrial metabolism promotes adaptation to proteotoxic stress.

Peter Tsvetkov, Alexandre Detappe, Kai Cai, Heather R Keys, Zarina Brune, Weiwen Ying, Prathapan Thiru, Mairead Reidy, Guillaume Kugener, Jordan Rossen and 9 more

Erratum issuedOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 392 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
392citing papers in PubMed, 5 pooled it
12.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

392 citing papers in PubMed, 5 syntheses or guidelines pooled it, 591 citations in OpenAlex.

  1. Pooled it
  2. Metabolic cell death in cancer: mechanisms and therapeutic potential.Apoptosis : an international journal on programmed cell death · 2025
    Pooled it
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  6. Article
  7. Cuproptosis and the bioinorganic basis of copper-induced cell death.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2026
    Review
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  13. Ferroptosis in gastrointestinal stromal tumors.Journal of gastrointestinal oncology · 2026
    Article
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332 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

19 authors at 8 institutions in 2 countries.

Peter TsvetkovBroad Institute of Harvard and MIT, Cambridge, MA, USA. ptsvetko@broadinstitute.org.ORCID http://orcid.org/0000-0002-7577-2342
Alexandre DetappeDana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-9364-1621
Kai CaiBiochemistry Department, University of Wisconsin-Madison, Madison, WI, USA.
Heather R KeysWhitehead Institute for Biomedical Research, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1371-2288
Zarina BruneWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Weiwen YingOnTarget Pharmaceutical Consulting LLC, Lexington, MA, USA.
Prathapan ThiruWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Mairead ReidyDana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Guillaume KugenerBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Jordan RossenBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Mustafa KocakBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Nora KoryWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Aviad TsherniakBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-3797-1877
Sandro SantagataDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7528-9668
Luke WhitesellWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Irene M GhobrialDana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
John L MarkleyBiochemistry Department, University of Wisconsin-Madison, Madison, WI, USA.
Susan LindquistWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Todd R GolubBroad Institute of Harvard and MIT, Cambridge, MA, USA. golub@broadinstitute.org.ORCID http://orcid.org/0000-0003-0113-2403
Broad Institute · USWhitehead Institute for Biomedical Research · USHarvard University · USUniversity of Wisconsin–Madison · USBrigham and Women's Hospital · USHoward Hughes Medical Institute · USTarget (United States) · USUniversity of Toronto · CA

Funding

TR&D 3: TECHNOLOGY DEVELOPMENT FOR NMR STUDIES OF SMALL MOLECULES (METABOLOMICS, NATURAL PRODUCTS, METABOLITE-PROTEIN INTERACTIONS) pp.537-585 P41GM103399 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI MARKLEY, JOHN LUTE · 2012 to 2019
$9.4M
Biogenesis of human mitochondrial iron-sulfur proteinsR01GM127666 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI MARKLEY, JOHN LUTE · 2019 to 2020
$719k
Howard Hughes Medical InstituteNIGMS NIH HHS P41 GM103399NIGMS NIH HHS R01 GM127666
6 · The paper itself

Abstract

The mechanisms by which cells adapt to proteotoxic stress are largely unknown, but are key to understanding how tumor cells, particularly in vivo, are largely resistant to proteasome inhibitors. Analysis of cancer cell lines, mouse xenografts and patient-derived tumor samples all showed an association between mitochondrial metabolism and proteasome inhibitor sensitivity. When cells were forced to use oxidative phosphorylation rather than glycolysis, they became proteasome-inhibitor resistant. This mitochondrial state, however, creates a unique vulnerability: sensitivity to the small molecule compound elesclomol. Genome-wide CRISPR-Cas9 screening showed that a single gene, encoding the mitochondrial reductase FDX1, could rescue elesclomol-induced cell death. Enzymatic function and nuclear-magnetic-resonance-based analyses further showed that FDX1 is the direct target of elesclomol, which promotes a unique form of copper-dependent cell death. These studies explain a fundamental mechanism by which cells adapt to proteotoxic stress and suggest strategies to mitigate proteasome inhibitor resistance.

Indexed as

AnimalsCells, CulturedCell SurvivalHumansMiceMitochondriaOxidative StressProteasome InhibitorsSmall Molecule LibrariesProteasome InhibitorsSmall Molecule Libraries

Identifiers

PMID31133756
PMCPMC8183600
OpenAlexW2945294912

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.