Lin Yumeng, Yang Bowen, Huang Yibo, Zhang You, Jiang Yu, Ma Longyun, Shen Ying-Qiang
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China.
Cell Insight. 2023 Jul 22;2(4):100113. doi: 10.1016/j.cellin.2023.100113. eCollection 2023 Aug.
Mitochondrial DNA (mtDNA) encodes proteins and RNAs that are essential for mitochondrial function and cellular homeostasis, and participates in important processes of cellular bioenergetics and metabolism. Alterations in mtDNA are associated with various diseases, especially cancers, and are considered as biomarkers for some types of tumors. Moreover, mtDNA alterations have been found to affect the proliferation, progression and metastasis of cancer cells, as well as their interactions with the immune system and the tumor microenvironment (TME). The important role of mtDNA in cancer development makes it a significant target for cancer treatment. In recent years, many novel therapeutic methods targeting mtDNA have emerged. In this study, we first discussed how cancerogenesis is triggered by mtDNA mutations, including alterations in gene copy number, aberrant gene expression and epigenetic modifications. Then, we described in detail the mechanisms underlying the interactions between mtDNA and the extramitochondrial environment, which are crucial for understanding the efficacy and safety of mtDNA-targeted therapy. Next, we provided a comprehensive overview of the recent progress in cancer therapy strategies that target mtDNA. We classified them into two categories based on their mechanisms of action: indirect and direct targeting strategies. Indirect targeting strategies aimed to induce mtDNA damage and dysfunction by modulating pathways that are involved in mtDNA stability and integrity, while direct targeting strategies utilized molecules that can selectively bind to or cleave mtDNA to achieve the therapeutic efficacy. This study highlights the importance of mtDNA-targeted therapy in cancer treatment, and will provide insights for future research and development of targeted drugs and therapeutic strategies.
线粒体DNA（mtDNA）编码对线粒体功能和细胞稳态至关重要的蛋白质和RNA，并参与细胞生物能量学和代谢的重要过程。mtDNA的改变与多种疾病相关，尤其是癌症，并且被视为某些类型肿瘤的生物标志物。此外，已发现mtDNA改变会影响癌细胞的增殖、进展和转移，以及它们与免疫系统和肿瘤微环境（TME）的相互作用。mtDNA在癌症发展中的重要作用使其成为癌症治疗的重要靶点。近年来，出现了许多针对mtDNA的新型治疗方法。在本研究中，我们首先讨论了mtDNA突变如何引发癌症发生，包括基因拷贝数改变、异常基因表达和表观遗传修饰。然后，我们详细描述了mtDNA与线粒体外环境之间相互作用的潜在机制，这对于理解mtDNA靶向治疗的疗效和安全性至关重要。接下来，我们全面概述了针对mtDNA的癌症治疗策略的最新进展。我们根据其作用机制将它们分为两类：间接靶向策略和直接靶向策略。间接靶向策略旨在通过调节参与mtDNA稳定性和完整性的途径来诱导mtDNA损伤和功能障碍，而直接靶向策略则利用能够选择性结合或切割mtDNA的分子来实现治疗效果。本研究强调了mtDNA靶向治疗在癌症治疗中的重要性，并将为未来靶向药物和治疗策略的研发提供见解。
