Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells

Johanna M Anttila; Mariel Savelius; Linda Id; Daniel Nicorici; Juhi Somani; Antti O Hiltunen; Pauliina M Munne; Aino Peura; Martina Peltonen; July Aung; Ryan Awadhpersad; Ellisiv Nyhamar; Bina Prajapati; Hanna Ala-Hongisto; Prson Gautam; Mika J Välimäki; Topi A Tervonen; Karina Šapovalovaitė; Raman Devarajan; María Victoria Ruiz Pérez; Minna Mutka; Panu Kovanen; Laura Niinikoski; Tuomo Meretoja; Johanna Mattson; Päivi Heikkilä; Krister Wennerberg; Marie Arsenian-Henriksson; Jukka Westermarck; Tero Aittokallio; Andrei Goga; Christopher B Jackson; Anni I Nieminen; Juha Klefström

doi:10.1016/j.celrep.2026.117629

Complex I drives glutamine-dependent TCA cycle to support viability of MYC^high breast cancer cells

Cell Rep. 2026 Jul 2;45(7):117629. doi: 10.1016/j.celrep.2026.117629. Online ahead of print.

Authors

Johanna M Anttila¹, Mariel Savelius¹, Linda Id¹, Daniel Nicorici¹, Juhi Somani¹, Antti O Hiltunen¹, Pauliina M Munne¹, Aino Peura¹, Martina Peltonen¹, July Aung¹, Ryan Awadhpersad², Ellisiv Nyhamar¹, Bina Prajapati¹, Hanna Ala-Hongisto¹, Prson Gautam³, Mika J Välimäki¹, Topi A Tervonen¹, Karina Šapovalovaitė¹, Raman Devarajan¹, María Victoria Ruiz Pérez⁴, Minna Mutka⁵, Panu Kovanen⁵, Laura Niinikoski⁶, Tuomo Meretoja⁶, Johanna Mattson⁷, Päivi Heikkilä⁵, Krister Wennerberg⁸, Marie Arsenian-Henriksson⁴, Jukka Westermarck⁹, Tero Aittokallio¹⁰, Andrei Goga¹¹, Christopher B Jackson², Anni I Nieminen¹², Juha Klefström¹³

Affiliations

¹ Cancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Program Unit, Faculty of Medicine, University of Helsinki, PO Box 63 (Street address: Haartmaninkatu 8), 00014 University of Helsinki, Helsinki, Finland.
² Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
³ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Tukholmankatu 3, 00290 Helsinki, Finland.
⁴ Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, 17165 Solna, Sweden.
⁵ Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
⁶ Breast Surgery Unit, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
⁷ Department of Oncology, University of Helsinki & Helsinki University Hospital, Helsinki, Finland.
⁸ Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
⁹ Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6A, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
¹⁰ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Tukholmankatu 3, 00290 Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Institute for Cancer Research, Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, Oslo, Norway.
¹¹ Department of Cell & Tissue Biology and UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Avenue, UCSF Campus Box 0512, San Francisco, CA 94143, USA.
¹² Stem Cell and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹³ Cancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Program Unit, Faculty of Medicine, University of Helsinki, PO Box 63 (Street address: Haartmaninkatu 8), 00014 University of Helsinki, Helsinki, Finland; Department of Cell & Tissue Biology and UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Avenue, UCSF Campus Box 0512, San Francisco, CA 94143, USA; Finnish Cancer Institute, Helsinki, Finland; FICAN South, Helsinki University Hospital, Helsinki, Finland. Electronic address: juha.klefstrom@helsinki.fi.

PMID: 42397738
DOI: 10.1016/j.celrep.2026.117629

Abstract

In many cancers, stably elevated MYC levels drive sustained activation of anabolic programs and the cell cycle, creating opportunities for the synthetic-lethal targeting of MYC^high tumors. Enhanced mitochondrial respiration is a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD⁺ through complex I-mediated oxidation of NADH, supporting the anabolic demand of MYC-driven cells. Metabolic carbon tracing reveals that MYC shifts the TCA cycle carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD⁺-depleting complex I inhibitors promotes MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYC^high tumors, combined inhibition of complex I and glutaminolysis produces persistent suppression of tumor growth. Altogether, the elevated respiration of MYC^high cells supports a glutamine carbon-enriched TCA cycle that meets anabolic demand, rendering MYC^high tumors selectively vulnerable to mitochondrial respiration and glutaminolysis inhibitors.

Keywords: CP: cancer; CP: metabolism; MYC; TCA cycle; breast cancer; cancer; complex I; glutamine; metabolism; mitochondria; mitochondrial respiration.