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Janet Shaw

Professor of Biochemistry

B.A. University of California, Berkeley

Ph.D. University of California, Los Angeles

Research

References

shaw@biochem.utah.edu

Janet Shaw's Lab Page

Janet Shaw's PubMed Literature Search

Research

Eukaryotic cells contain many membrane-bound organelles, each with a characteristic shape and distribution. Our lab is interested in how organelles establish and maintain these features. We use yeast and mammalian cells to study how mitochondrial fission, fusion and transport regulate mitochondrial function and inheritance during cell division. Our studies are directly relevant to human heath and disease. Defects in these processes cause embryonic lethality in multicellular organisms and are linked to neurological disorders in humans.

In most cells, mitochondria are organized as highly branched tubular networks.  This network is dynamic, undergoing frequent fission and fusion events and moving around on cytoskeletal tracks.  Fission, fusion and transport are regulated by novel GTPases that are conserved from yeast to humans.

Mitochondrial Fission:  Our lab identified the first molecular mediator of mitochondrial fission, a dynamin-related GTPase called Dnm1p.  Dnm1p forms spirals on the outer mitochondrial membrane that ‘clip’ mitochondrial tubules into smaller pieces.  Two additional molecules, called Fis1p and Mdv1p, work together with Dnm1p during the fission reaction. We’ve used cellular, genetic and biochemical approaches to dissect sequential steps in the assembly of functional fission complexes containing all three proteins.  Studies of the mammalian homolog of Dnm1p suggest that fission catalyzed by this GTPase is essential for the release of cell death factors from mitochondria during apoptosis (Frank et al., 2001).  Thus, regulation of mitochondrial fission also plays an important role in controlling cell survival and programmed cell death.

Mitochondrial Fusion:  The Fzo1p GTPase is embedded in the outer mitochondrial membrane and mediates mitochondrial fusion.  Work from our lab and others indicates that Fzo1p forms a complex with itself and two additional proteins, Mgm1p and Ugo1p.  Interest in mitochondrial fusion has been stimulated by the finding that mutations in the human homologs of Mgm1p and Fzo1p cause neurological diseases called dominant optic atrophy and Charcot-Marie-Tooth Syndrome (Alexander, C. et al., and Delettre, C. et al., 2000; Lawson, V. and Flanigan, K., 2005; Kijima, K. et al., 2005, Bradbury, J., 2004; Zuchner, S. et al., 2004).  We collaborate with researchers in Human Genetics at the University of Utah to better understand why defects in mitochondrial fusion cause these disorders in humans.

Mitochondrial Transport:  Yeast Gem1p is an outer mitochondrial membrane protein with two GTPase domains and two calcium-binding motifs. When Gem1p is absent or mutated, both mitochondrial morphology and mitochondrial movement from mother to daughter cell during division are disrupted. New studies reveal that mammalian (Fransson et al., 2006) and insect (Guo et al., 2005; Glater et al., 2006) homologs of Gem1p recruit molecular motors that transport mitochondria along cytoskeletal tracks. Flies lacking Gem1p die early in development because mitochondria cannot be transported down axons to the synapse.  In budding yeast, mitochondrial transport may also be regulated by Gem1p, however, mitochondrial movement occurs on actin filaments rather than on microtubules. We are currently studying how Gem1p controls mitochondrial movement on different cytoskeletal elements in eukaryotes.

 

The Dnm1 and Fzo1 GTPases act in opposing fission and fusion pathways to maintain tubular mitochondrial networks. Yeast mitochondria labeled with the Green Fluorescent Protein (GFP) form a branched network of tubular membranes that continually divide and fuse (middle panel). Mitochondrial division/fission is regulated by the Dnm1 GTPase. Mitochondrial fusion is regulated by the Fzo1 GTPase. Mutations in the Dnm1 GTPase (dnm1D) block fission and lead to the fusion of mitochondrial tips with each other and the sides of other tubules, forming elaborate "net" structures (left panel); Mutations in the Fzo1 GTPase (fzo1D) block fusion and lead to fragmentation of the mitochondrial network due to ongoing fission (right panel). The mother cell is in the bottom of each panel and the yeast daughter cell or 'bud' is in the top of each panel.

References