Fig. 2

Schematic representation of Drp1-mediated multi-step processes during mitochondrial fission. ① Emergence of mtDNA bad sectors. Damaged mitochondria undergo peripheral fission, whose contraction sites are marked by non-replicating mtDNA. ② Lyso-Drp1 mediated mitochondrial peripheral fission. Lyso-Drp1 interacts with Zip1 to promote Zn²⁺ removal through the Zip1-MCU channel. ③ ER-Drp1 mediated-actin bundling. Activated ER-Drp1 dimers promote the efficiency of ER winding around mitochondria by aggregating actin into bundles through Shrm4 binding. ④ ER-Drp1-driven mitochondrial pre-contraction. Mito-Drp1 adapters migrate to the ER-Drp1-driven mitochondrial pre-contraction site. ⑤ Mito-Drp1-mediated IMM fission. Cyto-Drp1 aggregates into the Mito-Drp1 polymer loop at the ER-Mito contact site, destroying the MCU on the IMM before outer membrane fission. ⑥ Mito-Drp1 and Golgi-derived PI(4)P vesicle co-mediated MOM fission. Mito-Drp1 polymer loop further contracts and cleaves the MOM via GTP hydrolysis. The recruitment of Golgi-derived vesicles is involved in this process. ⑦ Mito-Drp1 separation into the cytoplasm. Mito-Drp1 separates from cyclin C and is reconverted to Cyto-Drp1 tetramers/dimers with low GTPase activity. Drp1 Dynamin-related protein 1, IMM inner mitochondrial membrane, MCU mitochondrial calcium uniporter, MOM mitochondrial outer membrane, TBC1D15 TBC domain family member 15, OMM outer mitochondrial membrane, Cyto-Drp1 cytoplasmic Drp1, Lyso-Drp1 lysosome Drp1, ER-Drp1 endoplasmic reticulum-Drp1, Mito-Drp1 mitochondrial Drp1, Fis1 mitochondrial fission protein 1, MMP mitochondrial membrane potential, ROS reactive oxygen species, NLRP3 NOD-, LRR- and pyrin domain-containing protein 3, ER endoplasmic reticulum, mtDNA mitochondrial DNA, MFF mitochondrial fission factor, INF2 inverted formin 2, Shrm4 shroom4, PI(4)P phosphatidylinositol 4-phosphate