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Mammalian mitochondrial inner membrane fusion is mediated by OPA1(optic atrophy 1). Under physiological condition, OPA1 undergoes proteolytic processing to form a membrane-anchored long isoform (L-OPA1) and a soluble short isoform (S-OPA1). A combination of L-OPA1 and S-OPA1 are required for membrane fusion, however, the relevant mechanism is not well understood. In this study, we investigate the cryo-EM structures of S-OPA1 coated liposome at nucleotide-free and GTPγS bound states. S-OPA1 exhibits a general structure of dynamin family. It can assemble onto membrane in a helical array with a building block of dimer and thus induce membrane tubulation. A predicted amphipathic helix is discovered to mediate the tubulation activity of S-OPA1. The binding of GTPγS triggers a conformational rotation between GTPase domain and stalk region, resulting the rearrangement of helical lattice and tube expansion. This observation is opposite to the behavior of other dynamin proteins, suggesting a unique role of S-OPA1 in the fusion of mitochondrial inner membrane. SIGNIFICANCE STATEMENT Mitochondria are highly dynamic cellular organelles that constitute a remarkably dynamic network. Such dynamic network is vital to keep homeostasis of cellular metabolism and it is balanced by fission and fusion events. Having the double membrane, the fusion of mitochondria becomes more complicated in comparison with other cellular mono-membrane organelles. The inner membrane fusion is driven by OPA1 that needs to be pre-processed to long and short forms while the molecular mechanism is largely unknown. This work well characterizes the biochemical property of the short form of OPA1, and reveals how it interacts with membrane and how its conformation responds to nucleotide binding. This work gives a further insight into mitochondrial inner membrane fusion mechanism. |
