在母系-合子转化过程中，课题组人员观察到一个由泛素特异性肽酶30 （Usp30）调控的单主题mtDNA突变的纯化选择。在体外，Usp30抑制通过增加泛素介导的线粒体自噬（mitophagy）再现了这些发现。课题组人员还发现，高突变负担或异质性会损害泛素-蛋白酶体系统，这解释了突变如何逃避对catheme疾病的质量控制。抑制USP30释放潜伏的线粒体自噬，减少高异质性细胞中的突变mtDNA。这些发现提示了一种预防线粒体疾病的潜在策略。
研究人员表示，线粒体合成三磷酸腺苷对真核生物至关重要，但它依赖于两个基因组的合作：核DNA和线粒体DNA （mtDNA）。mtDNA的突变速度是核基因组的15倍，挑战了这种共生关系。机制已经发展到缓和mtDNA突变的影响，但了解甚少。
附：英文原文
Title: Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations
Author: Michele Frison, Brandon S. Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D. Ryall, Camilla Lyons, Stephen P. Burr, Malwina Prater, Lyuba V. Bozhilova, Angelos Glynos, James B. Stewart, Nick S. Jones, Marcos R. Chiaratti, Patrick F. Chinnery
Issue&Volume: 2025-10-09
Abstract: Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
DOI: adr5438
Source: https://www.science.org/doi/10.1126/science.adr5438