Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells.
Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells.
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DOI：
10.1186/2049-3002-1-11
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发表时间：
2013-03-18
影响因子：
5.9
通讯作者：
Porcelli AM
中科院分区：
文献类型：
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作者：
Calabrese C;Iommarini L;Kurelac I;Calvaruso MA;Capristo M;Lollini PL;Nanni P;Bergamini C;Nicoletti G;Giovanni CD;Ghelli A;Giorgio V;Caratozzolo MF;Marzano F;Manzari C;Betts CM;Carelli V;Ceccarelli C;Attimonelli M;Romeo G;Fato R;Rugolo M;Tullo A;Gasparre G;Porcelli AM
有氧糖酵解，即瓦尔堡效应，是癌细胞的主要标志。线粒体呼吸功能障碍被认为是这种糖酵解转变的主要原因之一。这一假设已经被重新审视，因为肿瘤似乎在进展过程中经历了基因调控的波动，其中一些依赖于功能性线粒体。在这个框架内，线粒体复合物I的作用仍有争议，特别是关于线粒体DNA突变在癌症代谢中的作用。这项工作的目的是提供概念证明，功能复合物I是维持肿瘤进展所必需的。复合物I-空骨肉瘤细胞与异位表达的复合物I亚单位1（MT-ND 1）互补。评估了复合物I重新组装和功能恢复，也评估了NADH消耗。测试克隆在软琼脂中生长和在裸鼠中产生肿瘤块的能力。通过哌莫硝唑染色和缺氧诱导因子-1 α（HIF-1α）免疫印迹和组织化学染色评估缺氧水平。454-进行焦磷酸测序以获得同种异体和非同种异体异种移植物的总体转录组学谱。在编码MT-ND 1的基因中的截短突变的互补表明，需要功能性酶来在缺氧反应期间进行糖酵解转变，并在体外和体内诱导瓦尔堡谱，从而促进癌症进展。这种触发由HIF-1α介导，其稳定性在α-酮戊二酸和琥珀酸之间的平衡恢复后受到调节，这是由于复合物I拯救后NADH消耗的恢复。呼吸复合物I对于诱导瓦尔堡效应和癌细胞对缺氧的适应是必不可少的，使它们能够维持肿瘤生长。因此，与其他线粒体肿瘤抑制基因不同，本文报道的复杂I型严重突变可能具有抗肿瘤特性，突出了此类遗传标记在癌症中的预后价值。
Aerobic glycolysis, namely the Warburg effect, is the main hallmark of cancer cells. Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift. This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression, some of which rely on functional mitochondria. In this framework, the role of mitochondrial complex I is still debated, in particular with respect to the effect of mitochondrial DNA mutations in cancer metabolism. The aim of this work is to provide the proof of concept that functional complex I is necessary to sustain tumor progression. Complex I-null osteosarcoma cells were complemented with allotopically expressed complex I subunit 1 (MT-ND1). Complex I re-assembly and function recovery, also in terms of NADH consumption, were assessed. Clones were tested for their ability to grow in soft agar and to generate tumor masses in nude mice. Hypoxia levels were evaluated via pimonidazole staining and hypoxia-inducible factor-1α (HIF-1α) immunoblotting and histochemical staining. 454-pyrosequencing was implemented to obtain global transcriptomic profiling of allotopic and non-allotopic xenografts. Complementation of a truncative mutation in the gene encoding MT-ND1, showed that a functional enzyme was required to perform the glycolytic shift during the hypoxia response and to induce a Warburg profile in vitro and in vivo, fostering cancer progression. Such trigger was mediated by HIF-1α, whose stabilization was regulated after recovery of the balance between α-ketoglutarate and succinate due to a recuperation of NADH consumption that followed complex I rescue. Respiratory complex I is essential for the induction of Warburg effect and adaptation to hypoxia of cancer cells, allowing them to sustain tumor growth. Differently from other mitochondrial tumor suppressor genes, therefore, a complex I severe mutation such as the one here reported may confer anti-tumorigenic properties, highlighting the prognostic values of such genetic markers in cancer.