Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer

Dysregulation of cellular metabolism is a hallmark of breast cancer progression and is associated with metastasis and therapeutic resistance. Here, we show that the breast tumor suppressor gene SIM2 promotes mitochondrial oxidative phosphorylation (OXPHOS) using breast cancer cell line models. Mechanistically, we found that SIM2s functions not as a transcription factor but localizes to mitochondria and directly interacts with the mitochondrial respiratory chain (MRC) to facilitate functional supercomplex (SC) formation. Loss of SIM2s expression disrupts SC formation through destabilization of MRC Complex III, leading to inhibition of electron transport, although Complex I (CI) activity is retained. A metabolomic analysis showed that knockout of SIM2s leads to a compensatory increase in ATP production through glycolysis and accelerated glutamine-driven TCA cycle production of NADH, creating a favorable environment for high cell proliferation. Our findings indicate that SIM2s is a novel stabilizing factor required for SC assembly, providing insight into the impact of the MRC on metabolic adaptation and breast cancer progression. Breast cancer: Possible route to blocking cancer progression Insights into the stabilising role of a metabolism-related protein could inform treatments that prevent breast cancer cells from proliferating. Oxidative phosphorylation is a metabolic process wherein cells use enzymes to metabolize nutrients, generating energy to produce adenosine triphosphate (ATP). Tumour cells actively reprogram such metabolic pathways to promote cancer progression. Weston Porter at Texas A&M University, College Station, USA, and co-workers examined the roles of the breast cancer suppressor gene singleminded-2s ( SIM2s ), in breast cell lines. In normal cells, SIM2s localises to the mitochondria and interacts with the mitochondrial respiratory chain (the complex involved in generating ATP) to create a supercomplex that promotes oxidative phosphorylation. Loss of SIM2s in breast cancer destabilizes supercomplex formation, resulting in compensatory ATP production via another pathway controlled by the tumour, feeding cancer progression.