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

Abstract

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.

Mitochondrial enzyme FAHD1 reduces ROS in osteosarcoma

“…Remarkably, discrepancies in ROS levels and other data are only apparent when normalized to mitochondrial copy numbers. Similar findings were observed when examining the impact of FAHD1 depletion in breast cancer cells 22 . Consequently, our data indicates that cells compensate for mitochondrial disruptions resulting from either the loss or elevation of FAHD1 levels by increasing mitochondrial numbers.…”

“…Connected to this, the malic enzyme (ME) couples mitochondria with aerobic glycolysis, especially in osteoblasts 49 . Of interest, previous studies on FAHD1 knockdown in breast cancer cells also observed regulations in GLS 22 . While a downregulation of KGA was observed in U2OS cells overexpressing the FAHD1 wildtype, an upregulation was noted in U2OS cells overexpressing the T192S variant.…”

“…Thus, the observed differences in growth could be attributed to the absence of these vital nutrients. It's crucial to account for such effects to elucidate specific metabolic regulations, a principle we have previously investigated in another study 22 . The remaining glucose the default serum is in part sufficient to sustain proper cell growth in U2OS, which is not the case with dialyzed serum, while withdrawal of glutamine is not tolerated.…”

“…Prior research has underscored the significant role of the enzyme FAHD1 in the metabolism of various cell types, tissues, and organisms 22 – 25 . FAHD1 exhibits highest expression levels in the kidney and liver 26 , and its expression appears to correlate with tissue dependence on calcium 15 .…”

“…It is proposed that FAHD1 activity as ODx contributes to the regulation of this node, potentially acting antagonistically to the PC reaction. Specifically, the hypothesis is that increased levels of oxaloacetate (resulting from FAHD1 depletion) may directly inhibit SDH activity 22 , 23 , decreased levels of oxaloacetate (resulting from increased FAHD1 activity) may disrupt the PEP-PYR-OAA cycle, consequently reducing mtGDP levels and indirectly inhibiting SDH activity 23 . Decreased levels of oxaloacetate may be restored in the cytosol through various pathways, such as lactate fermentation or pathways generating malate as a precursor metabolite 51 .…”