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Cited by 1Cancer, Hypoxia, and MetabolismCancer, Lipids, and MetabolismMetabolism, Diabetes, and Cancer

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Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

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Papadopoli, David, Palia, Ranveer, Jovanovic, Predrag, Tabariès, Sébastien, Ciccolini, Emma, Sabourin, Valerie, Igelmann, Sebastian, McLaughlan, Shannon, Zhan, Lesley, Kim, HaEun, Chekkal, Nabila, Szkop, Krzysztof J, Bertomeu, Thierry, Zeng, Jibin, Vassalakis, Julia, Afzali, Farzaneh, Mzoughi, Slim, Guccione, Ernesto, Tyers, Mike, Avizonis, Daina, Larsson, Ola, Postovit, Lynne-Marie, Djuranovic, Sergej, Ursini-Siegel, Josie, Siegel, Peter M, Pollak, Michael, Topisirovic, Ivan·2026·eLife
DOI 10.7554/elife.106587.3

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Abstract

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.

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Metadata

Authors
Papadopoli, D., Palia, R., Jovanovic, P., Tabariès, S., Ciccolini, E., Sabourin, V., Igelmann, S., McLaughlan, S., Zhan, L., Kim, H., Chekkal, N., Szkop, K. J., Bertomeu, T., Zeng, J., Vassalakis, J., Afzali, F., Mzoughi, S., Guccione, E., Tyers, M., Avizonis, D., Larsson, O., Postovit, L.-M., Djuranovic, S., Ursini-Siegel, J., Siegel, P. M., Pollak, M., & Topisirovic, I.
Affiliations
  • Lady Davis Institute for Medical Research (CA)
  • Institut du cancer Rosalind & Morris Goodman (CA)
  • Lady Davis Institute, SMBD JGH, McGill University
  • VIB-KU Leuven Center for Cancer Biology (BE)
  • Science for Life Laboratory (SE)
  • Institute for Research in Immunology and Cancer (CA)
  • Queen's University (CA)
  • Tisch Cancer Institute (US)
  • University of Toronto (CA)
  • Department of Cell Biology and Physiology, Washington University School of Medicine
  • Gerald Bronfman Department of Oncology, McGill University
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2026-05-05
Volume
14
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.106587.3
OpenAlex
W4403763048
Cited by
1
References
2
Citations by year
2026: 1
FWCI
3.22
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • eLife (acceptedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Mendeley Data (cc-by)
Funders
  • Canadian Institutes of Health Research (PJT-183843, PJT-479494, MFE-171312)
  • Terry Fox Research Institute (TFF-242122)
  • Cancer Research Society (NGS)
  • Canada Research Chairs (Tier 1)
  • Cancerfonden (22 2186)
  • Swedish Research Council (2020-01665)
  • the Cancer Research Funds Radiumhemmet (231263)
  • Queen's University
  • Fonds de Recherche du Québec – Santé (FRQS) Fellowships
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
ETFDH, multiple acyl-CoA dehydrogenase deficiency, cancer bioenergetics, oxidative phosphorylation, mTORC1, BCL6, 4E-BP1, Nalm-6 cells, acute lymphoblastic leukemia, tumor growth, metabolic reprogramming

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