IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-63892-3.html
   My bibliography  Save this article

Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling

Author

Listed:
  • Jung Seok Hwang

    (Emory University School of Medicine)

  • JiHoon Kang

    (Emory University School of Medicine)

  • Jaehyun Kim

    (Emory University School of Medicine)

  • Kiyoung Eun

    (Emory University School of Medicine)

  • Sophia West

    (Emory University School of Medicine)

  • Hannah E. Bacho

    (Emory University School of Medicine)

  • Vanessa Avalos

    (Emory University School of Medicine)

  • Sydney Shuff

    (Emory University School of Medicine)

  • Dong M. Shin

    (Emory University School of Medicine)

  • Nabil F. Saba

    (Emory University School of Medicine)

  • Kelly R. Magliocca

    (Emory University School of Medicine)

  • Cheng-Kui Qu

    (Emory University School of Medicine)

  • Haian Fu

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Suresh S. Ramalingam

    (Emory University School of Medicine)

  • Andrey A. Ivanov

    (Emory University School of Medicine)

  • Taro Hitosugi

    (Mayo Clinic)

  • Sumin Kang

    (Emory University School of Medicine)

Abstract

Chemotherapy is often a primary treatment for cancer. However, resistance leads to therapeutic failure. Acetylation dynamics play important regulatory roles in cancer cells, but the mechanisms by which acetylation mediates therapy resistance remain poorly understood. Here, using acetylome-focused RNA interference (RNAi) screening, we find that acetylation induced by mitochondrial dihydrolipoyl transacetylase (DLAT), independent of the pyruvate dehydrogenase complex, is pivotal in promoting resistance to chemotherapeutics, such as cisplatin. Mechanistically, DLAT acetylates methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) at lysine 44 and promotes 10-formyl-tetrahydrofolate (10-formyl-THF) and consequent mitochondrially encoded cytochrome c oxidase II (MT-CO2) induction. DLAT signaling is elevated in cancer patients refractory to chemotherapy or chemoimmunotherapy. A decoy peptide DMp39, designed to target DLAT signaling, effectively sensitizes cancer cells to cisplatin in patient-derived xenograft models. Collectively, our study reveals the crucial role of DLAT in shaping chemotherapy resistance, which involves an interplay between acetylation signaling and metabolic reprogramming, and offers a unique decoy peptide technology to overcome chemotherapy resistance.

Suggested Citation

  • Jung Seok Hwang & JiHoon Kang & Jaehyun Kim & Kiyoung Eun & Sophia West & Hannah E. Bacho & Vanessa Avalos & Sydney Shuff & Dong M. Shin & Nabil F. Saba & Kelly R. Magliocca & Cheng-Kui Qu & Haian Fu , 2025. "Non-canonical dihydrolipoyl transacetylase promotes chemotherapy resistance via mitochondrial tetrahydrofolate signaling," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63892-3
    DOI: 10.1038/s41467-025-63892-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-63892-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-63892-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Roland Nilsson & Mohit Jain & Nikhil Madhusudhan & Nina Gustafsson Sheppard & Laura Strittmatter & Caroline Kampf & Jenny Huang & Anna Asplund & Vamsi K. Mootha, 2014. "Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Natalia Pardo-Lorente & Anestis Gkanogiannis & Luca Cozzuto & Antoni Gañez Zapater & Lorena Espinar & Ritobrata Ghose & Jacqueline Severino & Laura García-López & Rabia Gül Aydin & Laura Martin & Mari, 2024. "Nuclear localization of MTHFD2 is required for correct mitosis progression," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Camilla Tombari & Alessandro Zannini & Rebecca Bertolio & Silvia Pedretti & Matteo Audano & Luca Triboli & Valeria Cancila & Davide Vacca & Manuel Caputo & Sara Donzelli & Ilenia Segatto & Simone Vodr, 2023. "Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Martha M. Zarou & Kevin M. Rattigan & Daniele Sarnello & Engy Shokry & Amy Dawson & Angela Ianniciello & Karen Dunn & Mhairi Copland & David Sumpton & Alexei Vazquez & G. Vignir Helgason, 2024. "Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. André Schultz & Amina A Qutub, 2016. "Reconstruction of Tissue-Specific Metabolic Networks Using CORDA," PLOS Computational Biology, Public Library of Science, vol. 12(3), pages 1-33, March.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63892-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.