mtDNA extramitochondrial replication mediates mitochondrial defect effects

Zhaoliang Shan; Shengnan Li; Yuxue Gao; Chunhua Jian; Xiuxiu Ti; Hui Zuo; Ying Wang; Guochun Zhao; Yan Wang; Qing Zhang

doi:10.1016/j.isci.2024.108970

mtDNA extramitochondrial replication mediates mitochondrial defect effects

iScience. 2024 Jan 19;27(2):108970. doi: 10.1016/j.isci.2024.108970. eCollection 2024 Feb 16.

Authors

Zhaoliang Shan¹, Shengnan Li¹, Yuxue Gao¹, Chunhua Jian¹, Xiuxiu Ti¹, Hui Zuo¹, Ying Wang¹, Guochun Zhao¹, Yan Wang², Qing Zhang¹

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing 210061, China.
² Department of Cardiovascular Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.

Abstract

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.

Keywords: Biological sciences; Molecular biology; Molecular genetics; Molecular interaction.