AIMS: Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2high disease. RESULTS: We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high cells to MitoTam is dependent on the mitochondrial fraction of Her2. INNOVATION: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. CONCLUSION: We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84-103.

• Keywords
• HER2, breast cancer, mitochondria, mitochondrially targeted tamoxifen, respirasome,
• MeSH
• Biomarkers MeSH
• Cell Death drug effects   MeSH
• Cell Respiration drug effects   MeSH
• Molecular Targeted Therapy MeSH
• Electron Transport Chain Complex Proteins antagonists & inhibitors   chemistry   metabolism   MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms drug therapy   metabolism   pathology   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Receptor, ErbB-2 antagonists & inhibitors   metabolism   MeSH
• Electron Transport Complex I antagonists & inhibitors   chemistry   metabolism   MeSH
• Tamoxifen pharmacology   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• Electron Transport Chain Complex Proteins MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH
• Receptor, ErbB-2 MeSH
• Electron Transport Complex I MeSH
• Tamoxifen MeSH

Mitochondrial complex II or succinate dehydrogenase (SDH) is at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. It has been shown that Sdh5 (SDHAF2/SDH5 in mammals) is required for flavination of the subunit Sdh1 (SDHA in human cells) in yeast. Here we demonstrate that in human breast cancer cells, SDHAF2/SDH5 is dispensable for SDHA flavination. In contrast to yeast, CRISPR-Cas9 nickase-mediated SDHAF2 KO breast cancer cells feature flavinated SDHA and retain fully assembled and functional complex II, as well as normal mitochondrial respiration. Our data show that SDHA flavination is independent of SDHAF2 in breast cancer cells, employing an alternative mechanism.

• Keywords
• SDH assembly factor, SDHA, SDHAF2, assembly factor, cancer biology, cancer cells, cell biology, complex II assembly, flavin adenine dinucleotide, flavination, flavinylation, mammal, mitochondria, mitochondrial complex II, mitochondrial respiratory chain complex, succinate dehydrogenase,
• MeSH
• Flavins MeSH
• Gene Knockdown Techniques MeSH
• Humans MeSH
• Mitochondrial Proteins genetics   metabolism   MeSH
• Mitochondria genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Breast Neoplasms genetics   metabolism   MeSH
• Protein Processing, Post-Translational * MeSH
• Electron Transport Complex II genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Flavins MeSH
• Mitochondrial Proteins MeSH
• Neoplasm Proteins MeSH
• Electron Transport Complex II MeSH
• SDHA protein, human MeSH Browser
• SDHAF2 protein, human MeSH Browser