An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2.
Mitochondrial fission is fundamentally important to cellular physiology. The dynamin-related protein Drp1 mediates fission, and interaction between mitochondrion and endoplasmic reticulum (ER) enhances fission. However, the mechanism for Drp1 recruitment to mitochondria is unclear, although previous results implicate actin involvement. Here, we found that actin polymerization through ER-localized inverted formin 2 (INF2) was required for efficient mitochondrial fission in mammalian cells. INF2 functioned upstream of Drp1. Actin filaments appeared to accumulate between mitochondria and INF2-enriched ER membranes at constriction sites. Thus, INF2-induced actin filaments may drive initial mitochondrial constriction, which allows Drp1-driven secondary constriction. Because INF2 mutations can lead to Charcot-Marie-Tooth disease, our results provide a potential cellular mechanism for this disease state.
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Farida
F
Korobova
Vinay
V
Ramabhadran
Henry N
HN
Higgs
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000199:Actins / Q000378:metabolism*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D034281:Dynamins; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D000080865:Formins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism; D041681:NIH 3T3 Cells; D055503:Protein Multimerization; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology
D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000080865:Formins; C546959:INF2 protein, human; C515509:INF2 protein, mouse; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D053778:Thiazolidines; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; C037068:latrunculin B