Quirós Pedro M, Español Yaiza, Acín-Pérez Rebeca, Rodríguez Francisco, Bárcena Clea, Watanabe Kenta, Calvo Enrique, Loureiro Marta, Fernández-García M Soledad, Fueyo Antonio, Vázquez Jesús, Enríquez José Antonio, López-Otín Carlos
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.
Cell Rep. 2014 Jul 24;8(2):542-56. doi: 10.1016/j.celrep.2014.06.018. Epub 2014 Jul 10.
We generated mice deficient in Lon protease (LONP1), a major enzyme of the mitochondrial quality control machinery. Homozygous deletion of Lonp1 causes early embryonic lethality, whereas its haploinsufficiency protects against colorectal and skin tumors. Furthermore, LONP1 knockdown inhibits cellular proliferation and tumor and metastasis formation, whereas its overexpression increases tumorigenesis. Clinical studies indicate that high levels of LONP1 are a poor prognosis marker in human colorectal cancer and melanoma. Additionally, functional analyses show that LONP1 plays a key role in metabolic reprogramming by remodeling OXPHOS complexes and protecting against senescence. Our findings demonstrate the relevance of LONP1 for cellular and organismal viability and identify this protease as a central regulator of mitochondrial activity in oncogenesis.
我们培育出了线粒体质量控制机制的主要酶——Lon蛋白酶（LONP1）缺陷的小鼠。Lonp1基因的纯合缺失会导致早期胚胎致死，而其单倍剂量不足则可预防结直肠癌和皮肤肿瘤。此外，LONP1基因敲低会抑制细胞增殖以及肿瘤形成和转移，而其过表达则会增加肿瘤发生。临床研究表明，LONP1的高表达是人类结直肠癌和黑色素瘤预后不良的标志物。此外，功能分析表明，LONP1通过重塑氧化磷酸化复合物和防止细胞衰老在代谢重编程中起关键作用。我们的研究结果证明了LONP1与细胞和机体活力的相关性，并确定这种蛋白酶是肿瘤发生中线粒体活性的核心调节因子。
