Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

1st Faculty of Medicine Charles University 121 08 Prague 2 Czech Republic

2nd Faculty of Medicine Charles University 150 06 Prague 5 Czech Republic

CCIBB Centre for Innovative Biomedicine and Biotechnology University of Coimbra 3060 197 Cantanhede Portugal

CNC UC Center for Neuroscience and Cell Biology University of Coimbra 3060 197 Cantanhede Portugal

Czech Centre for Phenogenomics Institute of Molecular Genetics Czech Academy of Sciences 142 20 Prague 4 Czech Republic

Department of Life and Environmental Sciences Polytechnic University of Marche 60131 Ancona Italy

Faculty of Science Charles University 128 00 Prague 2 Czech Republic

Institute of Biophysics and Informatics 1st Faculty of Medicine Charles University 121 08 Prague 4 Czech Republic

Institute of Biotechnology Czech Academy of Sciences 252 50 Vestec Czech Republic

Institute of Clinical and Experimental Medicine 140 21 Prague 4 Czech Republic

Institute of Experimental Medicine Czech Academy of Sciences 142 00 Prague 4 Czech Republic

Malaghan Institute of Medical Research Wellington 6242 New Zealand

PPDBEB Institute for Interdisciplinary Research Doctoral Programme in Experimental Biology and Biomedicine University of Coimbra 3060 197 Cantanhede Portugal

School of Pharmacy and Medical Science Griffith University Southport QLD 4222 Australia

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Oncogene. 2025 Jun 4. doi: 10.1038/s41388-025-03451-8. PubMed

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