A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division

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.

DOI: http://dx.doi.org/10.7554/eLife.08828.001

eLife digest

Mitochondria are structures within cells that provide the energy to power many biological processes that are essential for complex life. These structures are also highly dynamic and go through cycles of fission (in which a single mitochondrion splits in two) and fusion (in which two mitochondria merge into one). These processes both maintain the correct number of mitochondria in a cell and remove damaged ones, and defects in either can result in many diseases.

Previous research had shown that mitochondria are in close contact with another cellular structure called the endoplasmic reticulum. The points of contact mark the sites where mitochondria undergo fission, as small tubes of the endoplasmic reticulum wrap around, and then constrict, to split a mitochondrion.

Other recent work revealed that a protein called INF2 is anchored on the endoplasmic reticulum where it promotes mitochondrial constriction. This protein builds actin subunits into long filaments that provide the force for constriction. However, it was not clear how INF2 became active, and whether there are proteins on mitochondria that interact with INF2 or actin.

Manor, Bartholomew et al. have now used a combination of microscopy-based methods and biochemical analysis to discover that a mitochondrial protein called Spire1C performs all of these roles. Spire1C is found on the outer membrane of mitochondria; it interacts with INF2 to drive the formation of actin filaments that constrict mitochondria. These results suggest that Spire1C bridges the endoplasmic reticulum with the network of actin filaments. Further experiments then showed that increasing Spire1C levels in cells resulted in the mitochondria becoming fragmented due to increased constriction. On the other hand, depleting Spire1C had the opposite effect and caused mitochondria to become unusually elongated. Following on from this work, the next challenge is to see if Spire1C is used differently or similarly in the different processes that involve mitochondrial fission.

DOI: http://dx.doi.org/10.7554/eLife.08828.002