Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
Sci Signal. 2021 Jan 5;14(664):eabc4436. doi: 10.1126/scisignal.abc4436.
Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
了解沃伯格（Warburg）向有氧糖酵解转变的机制对于确定癌症的代谢基础至关重要。遗传性平滑肌瘤病和肾细胞癌（HLRCC）是一种侵袭性癌症，其特征是编码克雷布斯循环酶富马酸水合酶的基因发生双等位基因失活，早期发生有氧糖酵解，并迅速转移。我们观察到 HLRCC 患者的肿瘤中线粒体呼吸链受损。生化和转录组学分析显示，肿瘤中的呼吸链功能障碍是由于线粒体 DNA（mtDNA）编码的呼吸链复合物亚基的表达缺失所致，这是由于 mtDNA 含量明显减少和 mtDNA 突变增加所致。我们证明，HLRCC 肿瘤中富马酸的积累使负责 mtDNA 复制和校对的核心因子失活，导致呼吸链成分丧失，从而促进有氧糖酵解，并在这个葡萄糖依赖性人类癌症的典型模型中促进疾病进展。
