Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine, Texas A&M University, College Station, TX, 77843, USA.
Center for Toxicology and Environmental Health, North Little Rock, AR, 72118, USA.
Exp Mol Med. 2023 May;55(5):1046-1063. doi: 10.1038/s12276-023-00996-0. Epub 2023 May 1.
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.
细胞代谢失调是乳腺癌进展的一个标志，与转移和治疗抵抗有关。在这里，我们通过乳腺癌细胞系模型表明，乳腺肿瘤抑制基因 SIM2 促进线粒体氧化磷酸化 (OXPHOS)。从机制上讲，我们发现 SIM2 的功能不是作为转录因子，而是定位于线粒体，并直接与线粒体呼吸链 (MRC) 相互作用，促进功能性超级复合物 (SC) 的形成。SIM2s 表达的缺失通过破坏 MRC 复合物 III 的稳定性破坏 SC 的形成，导致电子传递抑制，尽管复合物 I (CI) 活性得以保留。代谢组学分析表明，SIM2s 的敲除导致通过糖酵解产生 ATP 的代偿性增加，以及加速谷氨酰胺驱动的 TCA 循环产生 NADH，为高细胞增殖创造了有利环境。我们的研究结果表明，SIM2s 是 SC 组装所必需的新型稳定因子，为 MRC 对代谢适应和乳腺癌进展的影响提供了深入了解。
