Kobayashi Hiroshi, Imanaka Shogo
Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara, Nara 634‑0813, Japan.
Int J Mol Med. 2025 Aug;56(2). doi: 10.3892/ijmm.2025.5559. Epub 2025 Jun 6.
Mitochondria and mitochondrial DNA (mtDNA) are crucial for cellular energy metabolism and the adaptive response to environmental changes. mtDNA collaborates with the nuclear genome to regulate mitochondrial function. Dysfunctional mitochondria and mutations in mtDNA are implicated in a wide range of diseases, including mitochondrial disorders, neurodegenerative conditions, age‑associated pathologies and cancer. While the nuclear genome has been extensively studied for its role in driving the clonal expansion of oncogenes and other aging‑related genetic alterations, knowledge regarding mtDNA remains comparatively limited. However, advances in quantitative analysis have provided information regarding the complex patterns of mtDNA mutations. The present review offers a detailed examination of mtDNA mutations and their classifications in the contexts of aging and cancer, and elucidates the role of mtDNA mutations in these processes. Mutations in mtDNA can be detected as early as the neonatal stage, yet most transition mutations retain a normal cellular phenotype. In contrast to mutations in oncogenes and tumor suppressor genes within the nuclear genome, mtDNA exhibits conserved mutational signatures, irrespective of cancer tissue origin. To adapt to the aging process, mitochondria undergo clonal expansion of advantageous mtDNA mutations, maintaining a dynamic equilibrium among various mitochondrial clones. Over time, however, the loss of strand bias can disrupt this equilibrium, diminishing the pool of adaptive clones. This breakdown in mitochondrial homeostasis may contribute to tumorigenesis. In conclusion, the heterogeneity of mtDNA mutations and the collapse of its homeostasis are pivotal in the progression of age‑related diseases, including cancer, underscoring the importance of mtDNA mutations in health and disease.
线粒体和线粒体DNA（mtDNA）对于细胞能量代谢以及对环境变化的适应性反应至关重要。mtDNA与核基因组协同作用以调节线粒体功能。功能失调的线粒体和mtDNA突变与多种疾病有关，包括线粒体疾病、神经退行性疾病、与年龄相关的病理状况和癌症。虽然核基因组在驱动癌基因的克隆扩增和其他与衰老相关的基因改变中的作用已得到广泛研究，但关于mtDNA的知识仍然相对有限。然而，定量分析的进展提供了有关mtDNA突变复杂模式的信息。本综述详细探讨了mtDNA突变及其在衰老和癌症背景下的分类，并阐明了mtDNA突变在这些过程中的作用。mtDNA突变早在新生儿期就可被检测到，但大多数转换突变仍保持正常的细胞表型。与核基因组中的癌基因和肿瘤抑制基因的突变不同，mtDNA表现出保守的突变特征，而与癌症组织起源无关。为了适应衰老过程，线粒体经历有利的mtDNA突变的克隆扩增，在各种线粒体克隆之间保持动态平衡。然而，随着时间的推移，链偏性的丧失会破坏这种平衡，减少适应性克隆的数量。线粒体稳态的这种破坏可能有助于肿瘤发生。总之，mtDNA突变的异质性及其稳态的崩溃在包括癌症在内的与年龄相关疾病的进展中至关重要，突出了mtDNA突变在健康和疾病中的重要性。
