27 mei 2025: Bron: Nature Cell Biology volume 27, pages847–862 (2025)

ALDH4A1, een veel voorkomend enzym - eiwit binnen het zogeheten MPC complex, speelt een verrassende rol in het voorkomen van kanker. ALDH4A1, geïdentificeerd als een derde structurele component van het mitochondriale pyruvaatdragercomplex (MPC). Door een trimere samenstelling te vormen met MPC1 en MPC2, behoudt ALDH4A1 de integriteit van MPC en vergemakkelijkt het de import van pyruvaat in mitochondriën.

Zoals de onderzoekers schrijven: Met misschien wel belangrijkste dat toevoeging van UK5099 preventief zou werken in het voorkomen van kwaadaardige kankercellen en ALDH4A1 wordt verhoogd vertoont deze tumoronderdrukking door de activiteit van het MPC complex te behouden. Onze studie identificeert ALDH4A1 als een essentiële component van MPC voor de pyruvaat-mitochondriënimport, toegang tot de TCA-cyclus en tumoronderdrukking.

Stukje tekst vertaald uit een abstract waarin overigens behoorlijk wetenschappelijke taal wordt gebruikt en geen gemakkelijke taal voor de gewone burger, maar de publicatie komt uit Nature en is toch wel interessant m.i. :

Mitochondriale pyruvaatimport vormt een cruciale stap in het cellulaire energiemetabolisme en verbindt cytosolische glycolyse met mitochondriale oxidatieve fosforylering. Verstoringen in deze route kunnen de proliferatie van kankercellen bevorderen door cytosolisch pyruvaat te verhogen en het glycolytisch metabolisme te stimuleren, een fenomeen dat vaak wordt geassocieerd met het Warburg-effect.

Inzicht in hoe het MPC-complex de pyruvaatimport reguleert, kan metabole kwetsbaarheden bij kanker aan het licht brengen. MPC1 en MPC2, de belangrijkste subeenheden van het mitochondriale pyruvaattransportcomplex, fungeren als kanaal voor de pyruvaatinstroom in de mitochondriën. Tot nu toe waren er nog geen aanvullende regulerende componenten geïdentificeerd.

Zo ontdekten onderzoekers aan de Duke University Medical Center en de Wake Forest University School of Medicine bij dieronderzoek met muizen.

Zij concluderen:

Behandeling met de MPC-remmer UK5099 verstoorde de interactie tussen ALDH4A1 en het MPC-complex, terwijl MPC1/2-dimeren intact bleven. Dit suggereert dat de ALDH4A1-MPC-interface mogelijk geschikt is voor medicamenteuze behandeling.


Het abstract is gepubliceerd in Nature, maar voor het volledige studierapport moet betaald worden, echteer als u naasrt het abstract klikt op figures en references kunt u heel veel meer informatie lezen hoe de onderzoekers te werk zijn gegaan. Met misschien wel belangrijkste dat toevoeging van UK5099 preventief zou werken in het voorkomen van kwaadaardige kankercellen:
  • Article
  • Published: 

ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression

Nature Cell Biology volume 27, pages847–862 (2025)Cite this article

Abstract

MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1–MPC2 to maintain the integrity and oligomerization of MPC1–MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.

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Acknowledgements

We thank J.-C. Martinou for sharing several key plasmids in this study. We acknowledge the support of the Wake Forest Baptist Comprehensive Cancer Center Cell & Cellular Imaging & Flow Cytometry Shared Resources, supported by the National Cancer Institute’s Cancer Center Support Grant (P30CA012197). We also acknowledge the support of Proteomics Core from Duke University School of Medicine. This research was supported partly by start-ups from Wake Forest University School of Medicine and Duke University School of Medicine, Endowed Professor Funds from Anderson Discovery Professor for Cancer Research and Fred and Janet Sanfilippo Distinguished Professor, and NIH grants (R01CA256158, R01CA248037 and R01CA270617) to H.K.L. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne.

Authors and Affiliations

  1. Department of Pathology, Duke University Medical Center, Duke University School of Medicine, Durham, NC, USA

    Che-Chia Hsu, Rajesh Kumar Manne, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Chia-Yang Li & Hui-Kuan Lin

  2. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Bo-Syong Pan, Tingjin Chen & Hui-Kuan Lin

  3. International Ph.D. Program in Innovative Technology of Biomedical Engineering and Medical Devices, Ming Chi University of Technology, New Taipei City, Taiwan

    Chi-Yun Wang

  4. Research Center for Intelligent Medical Devices, Ming Chi University of Technology, New Taipei City, Taiwan

    Chi-Yun Wang

  5. Center for Translational Science, Cellular Biology and Pharmacology Department, The Herbert Wertheim College of Medicine, Florida International University, Port St. Lucie, FL, USA

    Yan Jin & Haiwei Gu

Contributions

C.-C.H., C.-Y.W., R.K.M. and H.-K.L. designed experiments and wrote and edited the manuscript. C.-C.H., C.-Y.W., R.K.M. and Z.C. performed experiments and analysed the data for all figures. C.-C.H., R.K.M., Z.C., V.P., R.K., L.B., B.-S.P., T.C., Y.-R.C, H.-E.W., Y.J., H.G. and C.-Y.L provided technical support, comments and suggestions.

Corresponding author

Correspondence to Hui-Kuan Lin.

Ethics declarations

Competing interests

H.K.L. is a consultant for Stablix, Inc. and Chang Gung University of Science and Technology. All other authors declare no competing interests.

Peer review

Peer review information

Nature Cell Biology thanks Luca Scorrano and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Additional information

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ALDH4A1, preventie, kanker voorkomen, Duke University Medical Center en de Wake Forest University School of Medicine, MPC complex, mitochondriën


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