Mitochondrial HER2 stimulates respiration and promotes tumorigenicity

Abstract

AbstractBackgroundAmplification 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.