Abstract
Fusion of mitochondrial outer membranes is crucial for proper organelle function and involves large GTPases called mitofusins. The discrete steps that allow mitochondria to attach to one another and merge their outer membranes are unknown. By combining an in vitro mitochondrial fusion assay with electron cryo-tomography (cryo-ET), we visualize the junction between attached mitochondria isolated from Saccharomyces cerevisiae and observe complexes that mediate this attachment. We find that cycles of GTP hydrolysis induce progressive formation of a docking ring structure around extended areas of contact. Further GTP hydrolysis triggers local outer membrane fusion at the periphery of the contact region. These findings unravel key features of mitofusin-dependent fusion of outer membranes and constitute an important advance in our understanding of how mitochondria connect and merge.
Highlights
Membrane fusion underlies fundamental biological processes such as fertilization, virus entry into host cells or intracellular protein trafficking
Mitochondrial fusion and fission both depend on large GTPases of the Dynamin-Related Protein (DRP) family (Labbeet al., 2014; Low and Lowe, 2010)
The in vitro mitochondrial fusion assay (Figure 1A) allows us to distinguish between discrete steps of the mitochondrial fusion process (Hoppins et al, 2009; Meeusen et al, 2006, 2004)
Summary
Membrane fusion underlies fundamental biological processes such as fertilization, virus entry into host cells or intracellular protein trafficking. Protein and lipid trafficking mainly involves SNAREs (Soluble N-ethyl maleimide sensitive factor Attachment protein Receptors) that are expressed on all intracellular compartments undergoing fusion except peroxisomes and mitochondria (Cai et al, 2007; Escobar-Henriques and Anton, 2013). Mitochondria constitute a remarkably dynamic network with an organization and ultra-structure that is regulated by fusion and fission of mitochondrial outer and inner membranes (Labbeet al., 2014; Westermann, 2010). Mitochondrial fusion and fission both depend on large GTPases of the Dynamin-Related Protein (DRP) family (Labbeet al., 2014; Low and Lowe, 2010). Soluble DRPs assemble into spirals around membrane compartments. Among the three families of transmembrane DRPs implicated in fusion, Mitofusins and OPA1 mediate fusion of the mitochondrial outer and inner membranes, respectively, whereas atlastins promote homotypic fusion of ER tubules (McNew et al, 2013).
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