mtDNA extramitochondrial replication mediates mitochondrial defect effects,iScience

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mtDNA extramitochondrial replication mediates mitochondrial defect effects
iScience ( IF 4.6 ) Pub Date : 2024-01-19 , DOI: 10.1016/j.isci.2024.108970
Zhaoliang Shan ₁ , Shengnan Li ₁ , Yuxue Gao ₁ , Chunhua Jian ₁ , Xiuxiu Ti ₁ , Hui Zuo ₁ , Ying Wang ₁ , Guochun Zhao ₁ , Yan Wang ₂ , Qing Zhang ₁

Affiliation

A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases.

中文翻译：

mtDNA 线粒体外复制介导线粒体缺陷效应

高比例的严重线粒体缺陷会导致多种人类线粒体疾病。然而，到目前为止，这种线粒体缺陷效应的体内拯救信号尚不清楚。在这里，我们通过敲低必需的线粒体基因 dMterf4 和 dMrps23 构建了果蝇线粒体缺陷模型。在全基因组 RNAi 筛选之后，我们发现敲低 Med8/Tfb4/mtSSB/PolG2/mtDNA-解旋酶挽救了 dMterf4/dMrps23 RNAi 介导的线粒体缺陷效应。非常令人惊讶的是，它们通过 Med8/Tfb4-mtSSB/PolG2/mtDNA-解旋酶轴驱动线粒体外的 mtDNA 复制，以扩增胞质 mtDNA，导致激活 cGAS-Sting 样 IMD 通路，部分介导 dMterf4/dMrps23 RNAi 触发的作用。此外，我们发现 Med8/Tfb4-mtSSB/PolG2/mtDNA-解旋酶轴还介导其他果蝇线粒体基因缺陷触发的功能障碍和果蝇衰老。总体而言，我们的研究将 Med8/Tfb4-mtSSB/PolG2/mtDNA-解旋酶轴划分为通过驱动 mtDNA 线粒体外复制介导线粒体缺陷效应的候选机制;该轴功能障碍可能用于许多线粒体和年龄相关疾病的潜在治疗。

更新日期：2024-01-19

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