线粒体是细胞新陈代谢的主要中心，并直接或间接参与细胞的几乎所有生物学过程。在线粒体疾病中，呼吸电子传递和氧化磷酸化（OXPHOS）受损引发代谢的补偿性重构，其类似于癌细胞的Warburg型代谢状态。转录因子MYC（或c-MYC）是癌症中代谢重构的主要调节因子，能够促进糖酵解、核苷酸合成和谷氨酰胺利用，这些代谢过程在线粒体疾病中也已知或预测为受影响的过程。尽管迄今为止并未得到广泛认可，但几种线粒体疾病的细胞和小鼠模型显示MYC及/或其典型的转录签名上调。此外，线粒体整合应激反应(mt-ISR)相关的基因表达和代谢物水平变化与MYC过度表达的特征显示显著重叠。除了作为代谢调节因子外，MYC促进细胞增殖，改变细胞周期动力学，尤其是在高表达水平下，促进复制应激和基因组不稳定性，并使细胞对凋亡敏感。因为细胞增殖需要能量和细胞生物量的翻倍，复制细胞对OXPHOS缺陷尤为敏感。另一方面，预测OXPHOS缺陷的复制细胞对高水平的MYC尤为脆弱，因为MYC能够使细胞逃避代谢检查点并加速细胞周期进程。事实上，最近的一些研究展示了OXPHOS缺陷中的细胞周期缺陷和核DNA损伤。在这里，我们概述了MYC调节的一些重要的依赖于线粒体的代谢途径，回顾了与线粒体疾病中MYC表达有关的现有文献，并推测OXPHOS缺陷可能如何引发其上调，并探讨了这对这些疾病的发病机制有何影响。版权所有 © 2023 Purhonen, Klefström 和 Kallijärvi.

The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.Copyright © 2023 Purhonen, Klefström and Kallijärvi.