Mgm1p, a dynamin-related GTPase, is essential for fusion of the mitochondrial outer membrane.
itochondria are polymorphic structures. These cellular centres of energy production and sites of numerous essential metabolic reactions possess common ultrastructural features and a conserved internal organization, yet exhibit greatly varying shapes even within the same cell. As well as the classic kidneybean-shaped structures committed to memory by every biology student, mitochondria are frequently found as long, snake-like tubules, branched reticula, and extended tubular networks stretching into the far reaches of the cell. In many cell types these elaborate mitochondrial webs are extremely dynamic, undergoing frequent fission and fusion of tubules, tubular branching, and redistribution of tubules throughout the cytoplasm. Such alterations in mitochondrial shape occur during normal cell growth, in certain pathological conditions, and during cellular differentiation and development, sometimes yielding highly specialized mitochondrial structures such as those found in muscle and sperm cells. In a recent issue of Nature Cell Biology, Bleazard et al. identify the protein Dnm1 as a key molecular mediator of changes in mitochondrial morphology. Although mitochondria have been recognized for many years to be dynamic residents of the eukaryotic cytoplasm, the mechanisms underlying alterations in mitochondrial morphology have only recently been uncovered. The first cellular components implicated in determining the shape of mitochondria emerged from the isolation and analysis of Saccharomyces cerevisiae mutants defective in mitochondrial distribution and morphology (mdm mutants). Proteins identified through the characterization of these mutants include Mdm1, an intermediate-filament-like protein that appears to be a constituent of a cytoskeletal scaffold, and three integral proteins of the mitochondrial outer membrane, Mdm10 (ref. 7), Mmm1 (ref. 8), and Mdm12 (ref. 9). Loss of Mdm1 function leads to fragmentation of mitochondrial tubules (as well as dramatic defects in mitochondrial inheritance during cell proliferation), whereas loss of any of the three outermembrane proteins causes defects in mitochondrial inheritance and collapse of the normal tubular mitochondrial network into one or a few giant spherical mitochondria. These spherical structures are rapidly converted into normal tubular mitochondria when expression of the outer-membrane proteins is restored, illustrating the dynamic character of the organelle and the dramatic effect of specific committed proteins on gross mitochondrial shape. The generation of complex mitochondrial morphologies depends on abundant fusion and fission of mitochondrial tubules. A key component in mitochondrial fusion emerged from an analysis of a Drosophila mutant defective in sperm formation. During normal spermatogenesis, spermatid mitochondria aggregate and fuse into a large, multilayered structure that resembles a slice of onion when viewed by electron microscopy. This fusion fails to occur in the fuzzy onions mutant, leading to an aberrant aggregated structure (the ‘fuzzy onion’) and a block in the formation of viable sperm. Hales and Fuller cloned the fuzzy onion gene and identified its product as a mitochondrial, GTP-binding protein expressed in spermatids at the time of mitochondrial fusion. Analysis of the yeast homologue of Fuzzy onions, Fzo1, provided further insight into the protein’s function by showing that it localizes to the mitochondrial outer membrane, with the bulk of M the protein’s mass, including the GTP-binding site, projecting into the extra-mitochondrial cytoplasm. Loss of Fzo1 function led to rapid fragmentation of mitochondrial tubules and loss of mitochondrial DNA. Additionally, mitochondrial fusion that normally occurs following mating of two yeast cells failed to take place in the cells mutant for Fzo1, demonstrating a direct role for this protein in the fusion process. Recent findings illuminate the function of another critical determinant of mitochondrial morphology in S. cerevisiae. In an earlier study, the mdm29 mutation was shown to cause dramatic changes in mitochondrial distribution and morphology. Mitochondria in S. cerevisiae are normally found in a broadly branched network that is evenly spread around the cellular periphery, but cells with the mdm29 mutation contain extended mitochondrial tubules collapsed along one side of the cell. mdm29 was mapped to DNM1, one of three yeast genes encoding dynamin-related proteins. This gene was originally identified by its homology to mammalian dynamin, a large GTPbinding protein that has a critical role in endocytosis. However, the influence of DNM1 on mitochondrial distribution and morphology was independent of possible defects in endocytosis, and the Dnm1 protein was largely localized to the mitochondrial surface. These findings were supported by an independent study of Drp1, the most similar vertebrate homologue of Dnm1, which was shown to play a part in mitochondrial distribution and morphology in mammalian cells in culture. Bleazard et al. have now provided striking new evidence that Dnm1 is a component required for mitochondrial fission. Three key findings support this conclusion. First, careful microscopic characterization revealed that mitochondria frequently form highly fenestrated, net-like structures in the absence of Dnm1. Although the origin of these nets is unclear, their complex structures indicate that they may result from the defective fission of branched tubules. Second, immunoelectron microscopic analysis of wild-type yeast localized Dnm1 to dis‘‘The web of our life is of