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PMID:26305500
| Citation |
Manor, U, Bartholomew, S, Golani, G, Christenson, E, Kozlov, M, Higgs, H, Spudich, J and Lippincott-Schwartz, J (2015) A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division. Elife 4 |
|---|---|
| Abstract |
Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction and division. We propose Spire1C cooperates with INF2 to regulate actin assembly at ER-mitochondrial contacts. Simulations support this model's feasibility and demonstrate polymerizing actin filaments can induce mitochondrial constriction. Thus, Spire1C is optimally positioned to serve as a molecular hub that links mitochondria to actin and the ER for regulation of mitochondrial division. |
| Links |
PubMed PMC4574297 Online version:10.7554/eLife.08828 |
| Keywords |
Animals; COS Cells; Cercopithecus aethiops; Cytoskeleton/metabolism; Endoplasmic Reticulum/metabolism; Gene Expression Regulation; Humans; Microfilament Proteins/metabolism; Mitochondria/genetics; Mitochondria/physiology; Mitochondrial Dynamics; Nuclear Proteins/metabolism; Protein Binding; Protein Isoforms/metabolism |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0031307: integral component of mitochondrial outer membrane |
ECO:0000314: |
C |
Figure 2A - Spire1C is localized at the periphery of the mitochondria. Figure 2D - fluorescence assay demonstrated that the N-terminus of Spire1C is exposed to the cytoplasm while the C-terminus is not |
complete | ||||
| GO:0090141: positive regulation of mitochondrial fission |
ECO:0000315: |
P |
Figure 4 |
complete | ||||
| GO:0090141: positive regulation of mitochondrial fission |
ECO:0000316: |
UniProtKB:Q27J81
|
P |
Figure 6C and 6D - cells with overexpression of either Spire1C or INF2 or both display short mitochondria, while cells with knocked down expression of INF2 or mutant Spire1C display tubular mitochondria |
complete | |||
| GO:0032233: positive regulation of actin filament bundle assembly |
ECO:0000315: |
P |
Figure 3 - cells with overexpression of Spire1C show increased actin assembly on mitochondria as compared to control, while cells with overexpression of mutant Spire1C do not show increased actin assembly on mitochondria as compared to control |
complete | ||||
| GO:0051639: actin filament network formation |
ECO:0000315: |
P |
Figure 3 - cells with overexpression of Spire1C show increased actin assembly on mitochondria as compared to control, while cells with overexpression of mutant Spire1C do not show increased actin assembly on mitochondria as compared to control |
complete | ||||
| GO:0090141: positive regulation of mitochondrial fission |
ECO:0000316: |
UniProtKB:D3Z495
|
P |
Figure 6C: Cells overexpressing active INF2 and Spire1C show shortened mitochondria as compared to control, while cells overexpressing INF2 and Spire1C that lacks the KIND domain show elongated, tubular mitochondria. Figure 6D: Cells overexpressing Spire1C treated with INF2 siRNA show elongated mitochondria as compared to cells treated with scrambled siRNA. |
complete | |||
| GO:0007015: actin filament organization |
ECO:0000315: |
P |
Figure 3 - cells with overexpression of Spire1C show increased actin assembly on mitochondria as compared to control, while cells with overexpression of mutant Spire1C do not show increased actin assembly on mitochondria as compared to control |
complete | ||||
| GO:0030041: actin filament polymerization |
ECO:0000315: |
P |
Figure 3 - cells with overexpression of Spire1C show increased actin assembly on mitochondria as compared to control, while cells with overexpression of mutant Spire1C do not show increased actin assembly on mitochondria as compared to control |
complete | ||||
| GO:0090141: positive regulation of mitochondrial fission |
ECO:0000315: |
P |
Figure 4 |
complete | ||||
| GO:0031307: integral component of mitochondrial outer membrane |
ECO:0000314: |
C |
Figure 2A - Spire1C is localized at the periphery of the mitochondria. Figure 2D - fluorescence assay demonstrated that the N-terminus of Spire1C is exposed to the cytoplasm while the C-terminus is not |
complete | ||||
Notes
See also
References
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