• Eliska Novotna, Mirko Milosevic, Dana Prukova, Silvia Magalhaes-Novais, Sarka Dvorakova, Kristina Dmytruk, Jakub Gemperle, Dagmar Zudova, Tereza Nickl, Marek Vrbacky, Daniel Rosel, Vlada Filimonenko, Jan Prochazka, Jan Brabek, Jiri Neuzil, Katerina Rohlenova, and Jakub Rohlena.
• Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic.
• Eur. J. Clin. Invest. 2024 Jun 1; 54 (6): e14174e14174.

BackgroundAmplification of HER2, a receptor tyrosine kinase and a breast cancer-linked oncogene, is associated with aggressive disease. HER2 protein is localised mostly at the cell membrane, but a fraction translocates to mitochondria. Whether and how mitochondrial HER2 contributes to tumorigenicity is currently unknown.MethodsWe enriched the mitochondrial (mt-)HER2 fraction in breast cancer cells using an N-terminal mitochondrial targeting sequence and analysed how this manipulation impacts bioenergetics and tumorigenic properties. The role of the tyrosine kinase activity of mt-HER2 was assessed in wild type, kinase-dead (K753M) and kinase-enhanced (V659E) mtHER2 constructs.ResultsWe document that mt-HER2 associates with the oxidative phosphorylation system, stimulates bioenergetics and promotes larger respiratory supercomplexes. mt-HER2 enhances proliferation and invasiveness in vitro and tumour growth and metastatic potential in vivo, in a kinase activity-dependent manner. On the other hand, constitutively active mt-HER2 provokes excessive mitochondria ROS generation, sensitises to cell death, and restricts growth of primary tumours, suggesting that regulation of HER2 activity in mitochondria is required for the maximal pro-tumorigenic effect.Conclusionsmt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance.© 2024 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

27 keywords...

hide…