Mitochondrial mutations and mitoepigenetics: Focus on regulation of oxidative stress-induced responses in breast cancers
Mitochondrial mutations and mitoepigenetics: Focus on regulation of oxidative stress-induced responses in breast cancers
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DOI：
10.1016/j.semcancer.2020.09.012
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发表时间：
2022-06-09
影响因子：
14.5
通讯作者：
Aliev, Gjumrakch
中科院分区：
文献类型：
--
作者：
Chen, Kuo;Lu, Pengwei;Aliev, Gjumrakch
线粒体DNA的表观遗传调控(MtDNA)是一个新兴且发展迅速的研究领域。与核DNA的调控相比，线粒体DNA的表观遗传调控机制(有丝分裂表观遗传学)仍然较少被研究。然而，线粒体信号指导着许多重要的细胞内过程，包括有氧呼吸、细胞凋亡、细胞增殖和生存、核酸合成和氧化应激。活性氧(ROS)级联反应的后期过程和相关的管理不善与癌症进展有关。已有研究表明，癌细胞中存在ROS/氧化应激介导的线粒体DNA修复系统和线粒体类核保护缺陷。此外，线粒体DNA容易受到体细胞突变造成的损伤，导致线粒体呼吸链和能量产生的功能障碍，从而促进ROS的进一步生成和致癌作用。线粒体蛋白质是由集体线粒体基因组编码的，线粒体基因组包括通过串扰连接的核基因组和线粒体基因组。最近的报道确定了集体线粒体基因组中的缺陷有助于乳腺癌的发生和发展。据报道，线粒体DNA的突变破坏及其过度增殖和缺失改变了核表观遗传格局。不平衡的线粒体表观遗传学和氧化磷酸化的逆向调节(OXPHOS)可以有效地促进癌细胞的存活。因此，几种线粒体靶向治疗药物(双胍、氧磷酶抑制剂、维生素E类似物和抗生素贝达奎兰)被建议用于乳腺癌患者的未来临床试验。然而，改变的有丝分裂表观遗传学和癌症相关的mtDNA突变之间的串扰机制在很大程度上仍然不清楚。因此，mtDNA突变和表观遗传修饰可作为乳腺癌早期诊断和靶向治疗的潜在分子标志物。这篇综述讨论了癌细胞中有丝分裂表观遗传调控的作用，以及线粒体DNA修饰作为新的抗癌靶点的潜在应用。
Epigenetic regulation of mitochondrial DNA (mtDNA) is an emerging and fast-developing field of research. Compared to regulation of nucler DNA, mechanisms of mtDNA epigenetic regulation (mitoepigenetics) remain less investigated. However, mitochondrial signaling directs various vital intracellular processes including aerobic respiration, apoptosis, cell proliferation and survival, nucleic acid synthesis, and oxidative stress. The later process and associated mismanagement of reactive oxygen species (ROS) cascade were associated with cancer progression. It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in mtDNA repair system and mitochondrial nucleoid protection. Furthermore, mtDNA is vulnerable to damage caused by somatic mutations, resulting in the dysfunction of the mitochondrial respiratory chain and energy production, which fosters further generation of ROS and promotes oncogenicity. Mitochondrial proteins are encoded by the collective mitochondrial genome that comprises both nuclear and mitochondrial genomes coupled by crosstalk. Recent reports determined the defects in the collective mitochondrial genome that are conducive to breast cancer initiation and progression. Mutational damage to mtDNA, as well as its overproliferation and deletions, were reported to alter the nuclear epigenetic landscape. Unbalanced mitoepigenetics and adverse regulation of oxidative phosphorylation (OXPHOS) can efficiently facilitate cancer cell survival. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear. Hence, mtDNA mutations and epigenetic modifications could be considered as potential molecular markers for early diagnosis and targeted therapy of breast cancer. This review discusses the role of mitoepigenetic regulation in cancer cells and potential employment of mtDNA modifications as novel anti-cancer targets.