Membrane fusion is required to establish the morphology and cellular distribution of the mitochondrial compartment. In Drosophila, mutations in the fuzzy onions (fzo) GTPase block a developmentally regulated mitochondrial fusion event during spermatogenesis. Here we report that the yeast orthologue of fuzzy onions, Fzo1p, plays a direct and conserved role in mitochondrial fusion. A conditional fzo1 mutation causes the mitochondrial reticulum to fragment and blocks mitochondrial fusion during yeast mating. Fzo1p is a mitochondrial integral membrane protein with its GTPase domain exposed to the cytoplasm. Point mutations that alter conserved residues in the GTPase domain do not affect Fzo1p localization but disrupt mitochondrial fusion. Suborganellar fractionation suggests that Fzo1p spans the outer and is tightly associated with the inner mitochondrial membrane. This topology may be required to coordinate the behavior of the two mitochondrial membranes during the fusion reaction. We propose that the fuzzy onions family of transmembrane GTPases act as molecular switches to regulate a key step in mitochondrial membrane docking and/or fusion.

The Saccharomyces cerevisiae Dnm1 protein is structurally related to dynamin, a GTPase required for membrane scission during endocytosis. Here we show that Dnm1p is essential for the maintenance of mitochondrial morphology. Disruption of the DNM1 gene causes the wild-type network of tubular mitochondrial membranes to collapse to one side of the cell but does not affect the morphology or distribution of other cytoplasmic organelles. Dnm1 proteins containing point mutations in the predicted GTP-binding domain or completely lacking the GTP-binding domain fail to rescue mitochondrial morphology defects in a dnm1 mutant and induce dominant mitochondrial morphology defects in wild-type cells. Indirect immunofluorescence reveals that Dnm1p is distributed in punctate structures at the cell cortex that colocalize with the mitochondrial compartment. These Dnm1p-containing structures remain associated with the spherical mitochondria found in an mdm10 mutant strain. In addition, a portion of Dnm1p cofractionates with mitochondrial membranes during differential sedimentation and sucrose gradient fractionation of wild-type cells. Our results demonstrate that Dnm1p is required for the cortical distribution of the mitochondrial network in yeast, a novel function for a dynamin-related protein.

Analysis of the complete genome sequence of Saccharomyces cerevisiae confirms and extends earlier evidence that a majority of yeast genes are not essential, at least under laboratory conditions. Many fail to yield a discernible mutant phenotype even when disrupted. Genes not subject to natural selection would accumulate inactivating mutations, so these ''cryptic'' genes must have functions that are overlooked by the standard methods of yeast genetics. Two explanations seem possible: (i) They have important functions only in environments not yet duplicated in the laboratory and would have conditional phenotypes if tested appropriately. (ii) They make small, but significant, contributions to fitness even under routine growth conditions, but the effects are not large enough to be detected by conventional methods. We have tested the second ''marginal benefit'' hypothesis by measuring the fitnesses of a random collection of disruption mutants in direct competition with their wild-type progenitor. A substantial majority of mutant strains that lack obvious defects nevertheless are at a significant selective disadvantage just growing on rich medium under normal conditions. This result has important implications for efforts to understand the functions of novel genes revealed by sequencing projects.

Models of corticostriatal motor circuitry have focused on the role of the circuit in the hemisphere of the motor cortex providing primary control (contralateral to the movement). We used functional magnetic resonance imaging and functional connectivity analyses to study circuit function in both the controlling and noncontrolling hemispheres. During the completion of a unilateral motor task with either hand, each putamen nucleus demonstrated strong coactivation with structures in both hemispheres. The putamen in the noncontrolling hemisphere (ipsilateral to the movement) coactivated more strongly with the controlling motor cortex than with the noncontrolling cortex. These findings suggest that the two corticostriatal circuits are functionally integrated. New circuit models based on functional connectivity may need to be developed.

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