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.

线粒体 DNA (mtDNA) 的表观遗传调控是一个新兴且快速发展的研究领域。与核 DNA 的调控相比，mtDNA 表观遗传调控机制（线粒体表观遗传学）的研究仍然较少。然而，线粒体信号传导指导各种重要的细胞内过程，包括有氧呼吸、细胞凋亡、细胞增殖和存活、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管理不善与癌症进展有关。已经证明癌细胞在 mtDNA 修复系统和线粒体类核保护中含有 ROS/氧化应激介导的缺陷。此外，mtDNA 易受体细胞突变造成的损害，导致线粒体呼吸链和能量产生功能障碍，从而促进活性氧的进一步产生并促进致癌性。线粒体蛋白由集体线粒体基因组编码，该基因组包括通过串扰耦合的核基因组和线粒体基因组。最近的报告确定了集体线粒体基因组中的缺陷，这些缺陷有助于乳腺癌的发生和发展。据报道，mtDNA 的突变损伤及其过度增殖和缺失会改变核表观遗传景观。不平衡的线粒体表观遗传学和氧化磷酸化（OXPHOS）的不利调节可以有效地促进癌细胞的存活。因此，几种线粒体靶向治疗剂（双胍类、OXPHOS 抑制剂、维生素 E 类似物、和抗生素贝达喹啉）被建议用于乳腺癌患者的未来临床试验。然而，改变的线粒体表观遗传学和癌症相关的 mtDNA 突变之间的串扰机制仍不清楚。因此，mtDNA突变和表观遗传修饰可以被认为是乳腺癌早期诊断和靶向治疗的潜在分子标志物。本综述讨论了线粒体表观遗传调控在癌细胞中的作用以及 mtDNA 修饰作为新型抗癌靶点的潜在用途。mtDNA突变和表观遗传修饰可被视为乳腺癌早期诊断和靶向治疗的潜在分子标志物。本综述讨论了线粒体表观遗传调控在癌细胞中的作用以及 mtDNA 修饰作为新型抗癌靶点的潜在用途。mtDNA突变和表观遗传修饰可被视为乳腺癌早期诊断和靶向治疗的潜在分子标志物。本综述讨论了线粒体表观遗传调控在癌细胞中的作用以及 mtDNA 修饰作为新型抗癌靶点的潜在用途。