Trends in Cell Biology
Volume 12, Issue 4, 1 April 2002, Pages 178-184
Journal home page for Trends in Cell Biology

Review
Mitochondrial dynamics and division in budding yeast

https://doi.org/10.1016/S0962-8924(01)02246-2Get rights and content

Abstract

Mitochondria adopt a variety of different shapes in eukaryotic cells, ranging from multiple, small compartments to elaborate tubular networks. The establishment and maintenance of different mitochondrial morphologies depends, in part, on the equilibrium between opposing fission and fusion events. Recent studies in yeast, flies, worms and mammalian cells indicate that three high-molecular-weight GTPases control mitochondrial membrane dynamics. One of these is a dynamin-related GTPase that acts on the outer mitochondrial membrane to regulate fission. Recently, genetic approaches in budding yeast have identified additional components of the fission machinery. These and other new findings suggest a common mechanism for membrane fission events that has been conserved and adapted during eukaryotic evolution.

Section snippets

Mitochondrial morphology and membrane dynamics

Although the mitochondrion is always surrounded by a double membrane, contains a DNA genome and specializes in the synthesis of ATP, studies using vital dyes and the green fluorescent protein indicate that the morphology of this organelle is different in different cell types and organisms 5, 6, 7. In some cells, mitochondria appear as small, bean-shaped compartments dispersed throughout the cytoplasm. In others, the organelles form elongated tubules or a single, highly branched reticulum.

Large GTPases regulate mitochondrial membrane remodeling

The first known molecular regulator of mitochondrial fusion, Fzo, was discovered in Drosophila melanogaster, where it is required for a developmentally regulated mitochondrial fusion event during spermatogenesis [16]. The function of Fzo in mitochondrial fusion has been conserved during evolution as homologs have been identified in a range of other organisms including yeasts, worms, plants and humans [16]. Detailed analysis of yeast Fzo1p provided a direct demonstration that this GTPase

Fission and the outer membrane GTPase Dnm1p

The role of the Dnm1p GTPase in mitochondrial dynamics was first uncovered in a screen for yeast mutants with defective mitochondrial morphology [8]. Subsequent studies (described above) suggested that loss of Dnm1p function blocked mitochondrial fission but allowed the fusion of mitochondrial tips to continue, resulting in the formation of elaborate net-like structures 9, 10. Most importantly, the mitochondrial fragmentation induced by a fzo1 mutation no longer occurred in cells containing a

New components of the outer membrane fission machinery

Recently, a genetic approach was used to identify novel molecules, called Mdv1/Fis2/Gag3/Net2 30, 31, 32, 33 and Fis1/Mdv2 30, 31, that work together with the Dnm1p GTPase during mitochondrial fission. Several lines of evidence show that Mdv1p (mitochondrial division 1) and Fis1p (fission 1) regulate fission. First, like dnm1 mutations, mdv1 and fis1 mutations block fission and result in the formation of interconnected mitochondrial nets 30, 31, 32, 33. Second, fis1 and mdv1 mutations block

Mdv1p is required for Dnm1p function but not Dnm1p assembly

Localization studies revealed that Mdv1p is not required for the assembly of Dnm1p on mitochondrial tubules 30, 31, 32, 33. In wild-type DNM1 MDV1 FIS1 cells, Dnm1p and Mdv1p localize together in complexes on the outer mitochondrial membrane that catalyze membrane fission (Fig. 4b,c) 30, 33. In cells lacking the Mdv1 protein (DNM1 mdv1 FIS1), both the number and the distribution of Dnm1p complexes on the outer mitochondrial membrane appear wild type (Fig. 4b) 30, 31, 32, 33. However, these

Fis1p is required for assembly of functional Dnm1p–Mdv1p complexes

The topology of Fis1p on the outer mitochondrial membrane suggests that this protein might be acting early in the fission pathway as a ‘receptor’ on which to assemble functional Dnm1p fission complexes. In vivo localization studies of Dnm1p in fis1 mutant cells confirmed this prediction (Fig. 4b). In contrast to both wild-type and mdv1-mutant cells, Dnm1p–Mdv1p division complexes fail to assemble correctly in the DNM1 MDV1 fis1 mutant and are instead present in a few large aggregates on the

Fis1p is required for a second function

A second, late function for Fis1p was suggested by Mdv1p localization studies [30]. In wild-type cells, Mdv1p assembles with Dnm1p in punctate structures associated with mitochondria (Fig. 4b,c). In cells lacking Dnm1p (dnm1 MDV1 FIS1), Mdv1p is no longer observed in punctate structures but, interestingly, is still associated tightly with mitochondria and distributed evenly on the outer membrane (Fig. 4c) 30, 32, 33. This interaction of Mdv1p with mitochondria depends on Fis1p function because,

Regulation by Dnm1p occurs via a multistep pathway

Based on the genetic and cellular studies described above, a molecular model for mitochondrial division can be proposed (Fig. 5). The pathway of mitochondrial division consists of slow and fast steps. Assembly of Dnm1p onto the cytoplasmic face of the outer mitochondrial membrane is currently the earliest recognizable event in the pathway (Fig. 5, top, step 1). Although Mdv1p is part of the Dnm1p complex that is assembled, Mdv1p is not required for the assembly event itself. By contrast, the

Concluding remarks

Now that some of the players are known and a basic pathway for mitochondrial division has been mapped out, studies aimed at dissecting the biochemical roles of Dnm1p, Mdv1p and Fis1p can begin. These investigations will require the development of in vitro assays that reconstitute individual steps in the fission pathway. Identification of the molecular machinery that coordinates the behavior of both membranes during fission and fusion will also be essential. It is clear that mitochondria have

Acknowledgements

We thank S. Sever for insightful discussions and past and present members of our labs for their hard work and contributions to this field. Research in the Shaw lab has been supported by grants from the NIH, ACS, NSF and the University of Utah Huntsman Cancer Institute. Research in the Nunnari lab has been supported by grants from the NIH and NSF.

References (36)

  • J Nunnari

    Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA

    Mol. Biol. Cell

    (1997)
  • D Otsuga

    The dynamin-related GTPase, Dnm1p, controls mitochondrial morphology in yeast

    J. Cell Biol.

    (1998)
  • W Bleazard

    The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast

    Nat. Cell Biol.

    (1999)
  • H Sesaki et al.

    Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape

    J. Cell Biol.

    (1999)
  • G.J Hermann

    Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p

    J. Cell Biol.

    (1998)
  • K Guan

    Normal mitochondrial structure and genome maintenance in yeast requires the dynamin-like product of the MGM1 gene

    Curr. Genet.

    (1993)
  • K Shepard et al.

    The yeast dynamin-like protein, Mgm1p, functions on the mitochondrial outer membrane to mediate mitochondrial inheritance

    J. Cell Biol.

    (1999)
  • E.D Wong

    The dynamin-related GTPase, Mgm1p, is an intermembrane space protein required for maintenance of fusion competent mitochondria

    J. Cell Biol.

    (2000)
  • Cited by (317)

    View all citing articles on Scopus
    View full text