Yeast Miro GTPase, Gem1p, regulates mitochondrial morphology via a novel pathway

Abstract

Cell signaling events elicit changes in mitochondrial shape and activity. However, few mitochondrial proteins that interact with signaling pathways have been identified. Candidates include the conserved mitochondrial Rho (Miro) family of proteins, which contain two GTPase domains flanking a pair of calcium-binding EF-hand motifs. We show that Gem1p (yeast Miro; encoded by YAL048C) is a tail-anchored outer mitochondrial membrane protein. Cells lacking Gem1p contain collapsed, globular, or grape-like mitochondria. We demonstrate that Gem1p is not an essential component of characterized pathways that regulate mitochondrial dynamics. Genetic studies indicate both GTPase domains and EF-hand motifs, which are exposed to the cytoplasm, are required for Gem1p function. Although overexpression of a mutant human Miro protein caused increased apoptotic activity in cultured cells (Fransson et al., 2003. J. Biol. Chem. 278:6495–6502), Gem1p is not required for pheromone-induced yeast cell death. Thus, Gem1p defines a novel mitochondrial morphology pathway which may integrate cell signaling events with mitochondrial dynamics.

Bidirectional Ca 2+ -dependent control of mitochondrial dynamics by the Miro GTPase

“…Previous studies have described Miro expression-dependent changes in mitochondrial morphology (22,24,25), which may be linked to the altered motility. In addition, the present results on the Ca 2ϩ sensitivity of Miro activity necessitated further studies of the Miro dependence of mitochondrial morphology determined by the balance between fusion and fission.…”

“…Miro interacts with the kinesin-binding proteins, GRIF-1/Milton 2 and OIP106/Milton 1, suggesting that Miro forms a link between the mitochondria and the trafficking apparatus of the microtubules (24,25). Both the GTPase domains and EF-hand motifs of Miro are exposed to the cytoplasm and are required for yeast Miro function in mitochondrial morphology (22). Here, we have tested the hypothesis that Miro serves as a Ca 2ϩ -sensitive regulator of mitochondrial motility and fusion-fission dynamics.…”

“…Both proteins consist of 618 amino acid residues and were found to be 60% identical (21). Miro is present in yeast (Gem1p) (22), Drosophila (dMiro) (23), and mammalian cells as well (21). Miro interacts with the kinesin-binding proteins, GRIF-1/Milton 2 and OIP106/Milton 1, suggesting that Miro forms a link between the mitochondria and the trafficking apparatus of the microtubules (24,25).…”

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

“…These proteins possess EF-hand domains, suggesting the ability to bind Ca 2 þ ; 44 interact with the kinesin partner Milton to regulate mitochondrial movement; 45 and once activated induce fragmentation and perinuclear aggregation of mitochondria. 44 Apoptosis. Mitochondria amplify apoptotic signals by releasing cytochrome c and other cofactors required to activate effector caspases.…”

A RHOse by any other name: a comparative analysis of animal and plant Rho GTPases

“…The N-terminal GTPase domain shows significant similarity towards Rho GTPases. In yeast, the Miro homolog Gem1p is localized to the outer mitochondrial membrane [10]. Yeast cells lacking Gem1p contain globular, collapsed or grapelike mitochondria, indicating a role for Gem1p in regulating mitochondrial morphology.…”