Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actin Cytoskeleton / metabolism*
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Actin Cytoskeleton / ultrastructure
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Actins / metabolism*
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Animals
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line, Tumor
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Dynamins
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum / ultrastructure
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Formins
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GTP Phosphohydrolases / metabolism
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Humans
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Mice
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Microtubule-Associated Proteins / metabolism
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Mitochondria / metabolism*
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Mitochondria / ultrastructure*
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Mitochondrial Dynamics*
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Mitochondrial Proteins / metabolism
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NIH 3T3 Cells
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Protein Multimerization
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RNA, Small Interfering
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Recombinant Fusion Proteins / metabolism
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Thiazolidines / pharmacology
Substances
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Actins
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Bridged Bicyclo Compounds, Heterocyclic
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Formins
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INF2 protein, human
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INF2 protein, mouse
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Microfilament Proteins
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Thiazolidines
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GTP Phosphohydrolases
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DNM1L protein, human
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Dynamins
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latrunculin B