Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III
Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III
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DOI：
10.1158/0008-5472.can-06-0171
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Romeo, Giovanni
中科院分区：
文献类型：
--
作者：
Bonora, Elena;Porcelli, Anna Maria;Romeo, Giovanni
嗜酸细胞肿瘤的特征在于具有异常线粒体积聚的细胞。为了评估肿瘤性嗜酸细胞中的线粒体功能，我们研究了甲状腺嗜酸细胞系XTC. UC 1，并将其与其他甲状腺非嗜酸细胞系进行了比较。只有XTC.UC1细胞无法在半乳糖中存活，这种情况迫使细胞仅依赖线粒体产生能量。在XTC. UC 1细胞中，由复合物I底物驱动的呼吸和线粒体ATP合成速率严重降低。此外，在这些细胞中的酶活性的复合物I和III显着降低，与对照相比，在强烈增强的生产活性氧。生成了携带XTC. UC 1线粒体DNA（mtDNA）的骨肉瘤源性线粒体细胞杂交体（胞质杂交体），以区分能量衰竭是否取决于线粒体或核DNA突变。在半乳糖培养基中，XTC. UC 1胞质杂交体克隆显示出与亲本XTC. UC 1相似的活力和ATP含量降低，清楚地表明存在mtDNA改变。XTC. UC 1 mtDNA测序鉴定出ND 1的移码突变和细胞色素B的非保守取代，这两个突变具有明确的致病潜力。总之，这是第一次证明XTC. UC 1的线粒体功能障碍是由于与mtDNA突变相关的复合物I/III缺陷，如通过将线粒体基因组的缺陷能量表型转移到胞质杂种中所证明的。
Oncocytic tumors are characterized by cells with an aberrant accumulation of mitochondria. To assess mitochondrial function in neoplastic oncocytic cells, we studied the thyroid oncocytic cell line XTC.UC1 and compared it with other thyroid non-oncocytic cell lines. Only XTC.UC1 cells were unable to survive in galactose, a condition forcing cells to rely solely on mitochondria for energy production. The rate of respiration and mitochondrial ATP synthesis driven by complex I substrates was severely reduced in XTC.UC1 cells. Furthermore, the enzymatic activity of complexes I and III was dramatically decreased in these cells compared with controls, in conjunction with a strongly enhanced production of reactive oxygen species. Osteosarcoma-derived transmitochondrial cell hybrids (cybrids) carrying XTC.UC1 mitochondrial DNA (mtDNA) were generated to discriminate whether the energetic failure depended on mitochondrial or nuclear DNA mutations. In galactose medium, XTC.UC1 cybrid clones showed reduced viability and ATP content, similarly to the parental XTC.UC1, clearly pointing to the existence of mtDNA alterations. Sequencing of XTC.UC1 mtDNA identified a frameshift mutation in ND1 and a nonconservative substitution in cytochrome b, two mutations with a clear pathogenic potential. In conclusion, this is the first demonstration that mitochondrial dysfunction of XTC.UC1 is due to a combined complex I/III defect associated with mtDNA mutations, as proven by the transfer of the defective energetic phenotype with the mitochondrial genome into the cybrids.