Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.
Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.
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DOI：
10.1126/scisignal.abc4436
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发表时间：
2021-01-05
影响因子：
7.3
通讯作者：
Linehan WM
中科院分区：
文献类型：
--
作者：
Crooks DR;Maio N;Lang M;Ricketts CJ;Vocke CD;Gurram S;Turan S;Kim YY;Cawthon GM;Sohelian F;De Val N;Pfeiffer RM;Jailwala P;Tandon M;Tran B;Fan TW;Lane AN;Ried T;Wangsa D;Malayeri AA;Merino MJ;Yang Y;Meier JL;Ball MW;Rouault TA;Srinivasan R;Linehan WM
了解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。遗传性子宫肌瘤病和肾细胞癌(HLRCC)是一种侵袭性癌症，其特征是编码Krebs循环酶富马酸水合酶的基因双等位基因失活，早期转变为有氧糖酵解，并迅速转移。我们观察到HLRCC患者肿瘤的线粒体呼吸链受损。生化和转录学分析表明，肿瘤中呼吸链功能障碍是由于线粒体DNA(MtDNA)编码的呼吸链复合体亚单位表达缺失，导致mtDNA含量显著下降和mtDNA突变增加。我们证明，在HLRCC肿瘤中富马酸的积累使负责复制和校对mtDNA的核心因子失活，导致呼吸链成分的丢失，从而在这个葡萄糖依赖的人类癌症的原型模型中促进向有氧糖酵解的转变和疾病的进展。缺乏富马酸水合酶的肾肿瘤由于线粒体DNA改变引起的代谢改变而变得具有侵袭性。代谢酶富马酸水合酶线粒体DNA缺乏的代谢转变区分了一种称为遗传性子宫肌瘤病和肾细胞癌(HLRCC)的侵袭性和致命性肾癌。克劳克斯等人。研究了HLRCC肿瘤快速生长和转移的分子基础。富马酸水合酶缺乏导致代谢产物富马酸的积累，导致参与线粒体DNA复制和校对的因子的修饰和失活。随后，线粒体DNA突变增加，导致线粒体丢失，代谢转向有氧糖酵解。因此，缺乏一种关键的代谢酶会导致线粒体功能障碍和代谢重排，从而促进肿瘤的进展和转移。
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 bi-allelic 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 HLRCC patients. 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. Kidney tumors lacking fumarate hydratase become aggressive due to a metabolic shift arising from altered mitochondrial DNA. A metabolic shift from altered mitochondrial DNA Deficiency in the metabolic enzyme fumarate hydratase distinguishes an aggressive and lethal form of kidney cancer called hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Crooks et al. investigated the molecular basis for why HLRCC tumors rapidly grow and metastasize. Deficiency in fumarate hydratase led to the accumulation of the metabolite fumarate, resulting in the modification and inactivation of factors involved in mitochondrial DNA replication and proofreading. Subsequently, mitochondrial DNA mutations increased, leading to loss of mitochondria and a metabolic shift to aerobic glycolysis. Thus, lack of a crucial metabolic enzyme leads to mitochondrial dysfunction and metabolic rewiring that promote tumor progression and metastasis.
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作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
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