The mitochondrial enzyme FAHD1 regulates complex II activity in breast cancer cells and is indispensable for basal BT‐20 cells in vitro

The mitochondrial enzyme fumarylacetoacetate hydrolase domain‐containing protein 1 (FAHD1) was identified to be upregulated in breast cancer tissues. Here, we show that FAHD1 is indispensable for the survival of BT‐20 cells, representing the basal breast cancer cell type. A lentiviral knock‐down of FAHD1 in the breast cancer cell lines MCF‐7 and BT‐20 results in lower succinate dehydrogenase (complex II) activity. In luminal MCF‐7 cells, this leads to reduced proliferation when cultured in medium containing only glutamine as the carbon source. Of note, both cell lines show attenuated protein levels of the enzyme glutaminase (GLS) which activates programmed cell death in BT‐20. These findings demonstrate that FAHD1 is crucial for the functionality of complex II in breast cancer cells and acts on glutaminolysis in the mitochondria. Depletion of the mitochondrial enzyme FAHD1 in breast cancer cells leads to metabolic stress and cell death in triple‐negative BT‑20 cells. We find indications for reduced complex II (succinate dehydrogenase) activity and attenuated glutaminase levels upon knockdown of FAHD1. These effects are relevant in glutamine‐affine cells, such as triple‐negative breast cancer cells, whereas luminal MCF‐7 cells tolerate the withdrawal of FAHD1 to a certain extent.