Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.

中文翻译：

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mtDNA和线粒体功能障碍的变化如何影响癌症和癌症治疗？挑战，机遇和模式。

编码线粒体成分的核基因中的几种突变与增加的癌症风险相关，甚至具有致病性，例如琥珀酸脱氢酶（SDHB，SDHC和SDHD基因）和异柠檬酸脱氢酶（IDH1和IDH2基因）。最近，研究表明线粒体DNA（mtDNA）突变在多种癌症的发生中起着重要作用。各种研究都将mtDNA异常与线粒体功能障碍相关联，包括突变，缺失，倒位和拷贝数改变。这可能解释了许多癌细胞类型中受阻的细胞生物能。生殖细胞（egm10398A> G; m.6253T> C）和体细胞mtDNA突变以及mtDNA拷贝数差异似乎与癌症风险有关。根据多重打击模型，mtDNA似乎可以作为驱动子或互补基因突变。如m.8993T> G所观察到的，这可以增强细胞的诱变/克隆潜力，或影响癌症进展后期的转移潜力。或者，其他mtDNA变异将是肿瘤中无辜的客体突变，因此对致瘤或转移潜能没有贡献。在这篇综述中，我们讨论了报告的mtDNA变异如何干扰癌症治疗以及这对当前成功的药物干预有何影响。据报道MT-ND4和mtDNA耗竭的突变与顺铂耐药有关。二甲双胍对OXPHOS的药物损害可以提高放疗的效率。为了研究癌症中的线粒体功能障碍，使用不同的细胞模型（例如ρ（0）细胞或cybrids），体内鼠模型（异种移植物和特定的mtDNA小鼠模型以及自发性癌症小鼠模型）和小动物模型（例如Danio rerio）可能会很有趣。对于未来的研究，我们预见到，揭示mtDNA变异可以有助于针对特定癌症类型的个性化治疗并改善疾病的预后。