Abstract
Mammalian mitochondrial inner membrane fusion is mediated by optic atrophy 1 (OPA1). Under physiological conditions, 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 is essential for efficient membrane fusion; however, the relevant mechanism is not well understood. In this study, we investigate the cryo-electron microscopic structures of S-OPA1-coated liposomes in nucleotide-free and GTPγS-bound states. S-OPA1 exhibits a general dynamin-like structure and can assemble onto membranes in a helical array with a dimer building block. We reveal that hydrophobic residues in its extended membrane-binding domain are critical for its tubulation activity. The binding of GTPγS triggers a conformational change and results in a rearrangement of the helical lattice and tube expansion similar to that of S-Mgm1. These observations indicate that S-OPA1 adopts a dynamin-like power stroke membrane remodeling mechanism during mitochondrial inner membrane fusion.
Highlights
In eukaryotic cells, series of discrete membranous compartments separate different biochemical reactions, and the membrane fission and fusion mechanisms accomplish communication between and within these compartments (McNew et al, 2013)
The liposomes were prepared with a phospholipid composition of 45% 1,2-dioleoylsn-glycero-3-phosphocholine, 22% 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 8% phosphatidylinositol and 25% cardiolipin, which approximately reflects the composition of the mitochondrial inner membrane (Ban et al, 2010)
By examining the mixture of S-optic atrophy 1 (OPA1) with a liposome using both negative-staining electron microscopy (nsEM) and cryo-electron microscopy (cryo-EM), we identified considerable tubulation of the liposomes induced by short-form OPA1 (S-OPA1) (Figure 1E and F)
Summary
Series of discrete membranous compartments separate different biochemical reactions, and the membrane fission and fusion mechanisms accomplish communication between and within these compartments (McNew et al, 2013). Mitochondria, which are double-membrane organelles, can form remarkable dynamic networks through membrane fusion and fission regulated by dynamins (Labbeet al., 2014; van der Bliek et al, 2013; Westermann, 2010). Among those dynamins, optic atrophy 1 (OPA1) is known to be related to mitochondrial inner membrane fusion (Anand et al, 2014; Frezza et al, 2006; MacVicar and Langer, 2016). L-OPA1 can be further cleaved into a soluble short-form OPA1 (S-OPA1) through the S1 or S2 site between the TM and the coiled-coil domain (Ishihara et al, 2006; Song et al, 2007) Both L-OPA1 and S-OPA1 participate in mitochondrial inner membrane fusion.
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