Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Mol Cell. 2019 May 2;74(3):452-465.e7. doi: 10.1016/j.molcel.2019.02.012. Epub 2019 Mar 14.
Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2.
高等真核生物中的信号多样性及其随后的复杂性部分可以通过一个基因编码的具有多种生化功能的多肽来解释，该多肽在不同的细胞环境中具有多种生化功能。例如，鼠双微体 2（MDM2）在功能上被特征化为癌基因和肿瘤抑制因子，但这种双重分类混淆了细胞生物学和临床文献。通过互补的生化、细胞器和细胞方法鉴定，我们报告 MDM2 负调节烟酰胺腺嘌呤二核苷酸：泛醌氧化还原酶 75 kDa Fe-S 蛋白 1（NDUFS1），导致线粒体呼吸减少、明显的氧化应激，并促使线粒体凋亡途径。MDM2 直接结合并隔离 NDUFS1，阻止其在线粒体中的定位，并最终导致复合物 I 和超复合物的不稳定以及氧化磷酸化效率降低。MDM2 的氨基末端区域足以结合 NDUFS1、改变超复合物组装并诱导细胞凋亡。最后，该途径独立于 p53，并且在表达转基因 Mdm2 的果蝇和小鼠模型中观察到几种线粒体表型。
