Two isoforms of a yeast GTPase combine—with the help of a special phospholipid—to drive mitochondrial inner membrane fusion, DeVay et al. report.
Mitochondria constantly merge and divide to distribute their activity appropriately throughout the cell. When coming together, these organelles use proteins related to the endocytic GTPase dynamin to fuse both their outer and inner membranes. In yeast, two different isoforms of a GTPase called Mgm1 drive inner membrane fusion: a short soluble form (s-Mgm1) that is proteolytically cleaved from a longer, transmembrane version (l-Mgm1). Both isoforms are required for fusion, but their precise contributions to the process were unclear.
DeVay et al. expressed the proteins and examined their association with liposomes mimicking either the mitochondrial inner or outer membranes. Both s-Mgm1 and l-Mgm1 preferred inner membrane liposomes—the key determinant was an inner membrane phospholipid called cardiolipin. Moreover, although s-Mgm1 on its own was monomeric and inactive, cardiolipin stimulated the protein's GTPase activity by promoting its oligomerization on the liposome surface. s-Mgm1 thus acts specifically at the inner membrane, despite its localization to the intermembrane space.
Cardiolipin didn't stimulate the activity of l-Mgm1, however, which fit the group's observation that yeast expressing GTPase-deficient l-Mgm1 were normal, as long as they expressed a separate version of s-Mgm1 that retained its enzymatic function. The researchers think that cardiolipin helps the two Mgm1 isoforms assemble together on the inner membrane, where the conformational changes in s-Mgm1 as it hydrolyses GTP are coupled to lipid bilayer deformation by l-Mgm1's transmembrane domain. In addition, l-Mgm1 dimers may tether opposing inner membranes together, as a prelude to fusion or to fold them into cristae.
