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Mitochondrial HER2 stimulates respiration and promotes tumorigenicity

E. Novotna, M. Milosevic, D. Prukova, S. Magalhaes-Novais, S. Dvorakova, K. Dmytruk, J. Gemperle, D. Zudova, T. Nickl, M. Vrbacky, D. Rosel, V. Filimonenko, J. Prochazka, J. Brabek, J. Neuzil, K. Rohlenova, J. Rohlena

. 2024 ; 54 (6) : e14174. [pub] 20240130

Language English Country England, Great Britain

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24013792

Grant support
21-04607X Grantová Agentura České Republiky
22-34507S Grantová Agentura České Republiky
5068-2022 European Molecular Biology Organization
NU23-03-00226 Agentura Pro Zdravotnický Výzkum České Republiky
1435320 Grantová Agentura, Univerzita Karlova
1506318 Grantová Agentura, Univerzita Karlova
RVO86652036 Czech Academy of Sciences
RVO68378050 Czech Academy of Sciences
Ministerstvo Školství, Mládeže a Tělovýchovy : LX22NPO5102 : LM2023036 : LM2023050
CZ.02.1.01/0.0/0.0/16_013/0001775 European Regional Development Fund
CZ.02.1.01/0.0/0.0/18_046/0016045 European Regional Development Fund

BACKGROUND: Amplification 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: mt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance.

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