MtDNA extramitochondrial replication mediates mitochondrial defect effects.

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 effec

SUBMITTER: Shan Z 

PROVIDER: S-EPMC10844862 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature