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Janet Shaw

Professor of Biochemistry

Mitochondrial Dynamics and Disease

Janet Shaw

 

Molecular Biology Program

Biological Chemistry Program

Education

B.A. University of California, Berkeley

Ph.D. University of California, Los Angeles

 

 

Research

The Shaw laboratory uses yeast, mammalian cells and mice to study how mitochondrial fission, fusion and movement regulate mitochondrial function and dysfunction in single cells and whole organisms. Our studies are directly relevant to human heath and disease. Defects in mitochondrial membrane dynamics cause embryonic lethality in multicellular organisms and inherited 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 man.

Mitochondrial Fission

Mitochondrial fission plays critical roles during development and the cell cycle and is also required for the turnover and degradation of damaged mitochondrial compartments. Our lab identified the first molecular mediator of mitochondrial fission, a dynamin-related GTPase called Dnm1.  Dnm1 forms spirals on the outer mitochondrial membrane that ‘clip’ mitochondrial tubules into smaller pieces.  Two additional molecules, called Fis1 and Mdv1, work together with Dnm1 during the fission reaction. We use a multidisciplinary approach to study how the multi-protein fission complex assembles, constricts and severs the mitochondrial membrane.

Mitochondrial Fusion

Mitochondrial fusion allows exchange of metabolites, proteins and mtDNA and is critical for optimal mitochondrial function. The Fzo1 GTPase is embedded in the outer mitochondrial membrane and mediates outer membrane fusion.  A second GTPase, Mgm1, mediates inner membrane fusion.  Mutations in the human homologs of Mgm1 and Fzo1 cause inherited neurological diseases including dominant optic atrophy and Charcot-Marie-Tooth Syndrome. We collaborate with researchers at the University of Utah and the National Institutes of Health to identify the molecular basis of these disorders in humans.

Mitochondrial Movement

Mitochondrial movement positions these organelles in all cells and is critical in highly polarized cells such as neurons. Miro proteins are large GTPases on the mitochondrial surface, which bind molecular motors that move mitochondria along cytoskeletal tracks. Mammals have two Miro homologs, Miro1 and Miro2. We have generated Miro knockout mice and are studying the role of Miro proteins in development and neuropathy.

 

Shaw Figure

Mitochondrial fusion in human fibroblast cells
Unfused mitochondria are red or green. Fused mitochondria are yellow. Nuclei are blue. (B. Amiott and P. Lott)

References

  1. Kalia R, Wang RY, Yusuf A, Thomas PV, Agard DA, Shaw JM, Frost A. (2018) Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature. 558(7710):401-405. 
  2. Schuler MH, Lewandowska A, Caprio GD, Skillern W, Upadhyayula S, Kirchhausen T, Shaw JM, Cunniff B. (2017) Miro1-mediated mitochondrial positioning shapes intracellular energy gradients required for cell migration. Mol Biol Cell. 28(16):2159-2169.
  3. Nguyen TT, Oh S-S, Weaver D, Lewandowska  A, Maxfield D, Schuler M-H, Smith NK, Macfarlane J, Saunders G, Palmer C A, Debattisti V, Koshiba T, Pulst SM, Feldman EL, Hajnóczky G, Shaw JM. (2014) Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci U S A, 111(35), E3631-40.
  4. Bui HT, Shaw JM (2013) Dynamin assembly strategies and adaptor proteins in mitochondrial fission. Curr Biol, 23(19), R891-9.
  5. Lewandowska A, Macfarlane J, Shaw JM (2013) Mitochondrial association, protein phosphorylation and degradation regulate the availability of the active Rab GTPase, Ypt11, for mitochondrial inheritance. Mol Biol Cell, 24(8), 1185-95.
  6. Koirala S, Guo Q*, Kalia R*, Bui HT, Eckert DM, Frost A**, Shaw JM** (2013) Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission. Proc Natl Acad Sci U S A, 110(15), E1342-51. *contributed equally; **co-communicating.
  7. Bui HT, Karren MA, Bhar D, Shaw JM (2012) A novel motif in the yeast mitochondrial dynamin Dnm1 is essential for adaptor binding and membrane recruitment. J Cell Biol, 199(4), 613-22. (Subject of JCB In this issue)
  8. Guo Q, Koirala S, Perkins EM, McCaffery JM, Shaw JM (2012) The mitochondrial fission adaptors Caf4 and Mdv1 are not functionally equivalent. PLoS One, 7(12), e53523.
  9. Nguyen TT*, Lewandowska A*, Choi JY*, Markgraf DF*, Junker M, Bilgin M, Ejsing CS, Voelker DR**, Rapoport TA**, Shaw JM** (2012) Gem1 and ERMES do not directly affect phosphatidylserine transport from ER to mitochondria or mitochondrial inheritance. Traffic, 13(6), 880-890. *contributed equally; **co-communicating.
  10. Cohen MM, Amiott EA, Day AR, Leboucher GP, Pryce EN, Glickman MH, McCaffery JM, Shaw JM, Weissman AM (2011) Sequential requirements for the GTPase domain of the mitofusion Fzo1 and the ubiquitin ligase SCFMdm30 in mitochondrial outer membrane fusion. J Cell Sci, 124(9), 1403-1410.
  11. Koshiba T*, Holman H, Kai Y, Kubara K, Kawabata S-I, Okamoto K, Shaw JM (2010) Mitochondrial Inheritance mediated by the yeast Miro protein Gem1 requires activities of both GTPase domains and EF-hand motifs. J Biol Chem, 286(1), 354-362. *communicating author
  12. Koirala S, Bui HT, Schubert HL, Eckert DM, Hill CP, Kay MS*, Shaw JM* (2010) Molecular architecture of a dynamin adaptor: implications for assembly of mitochondrial fission complexes. J Cell Biology, 191(6), 1127-39. *co-communicating authors. (This article was the subject of JCB In Focus)
  13. Amiott EA, Cohen MM, Saint-Georges Y, Weissman AM, Shaw JM (2009) A mutation associated with CMTA neuropathy causes defects in Fzo1 GTP hydrolysis, ubiquitylation, and protein turnover. Mol Biol Cell, 20(23), 5026-5035. (This article was featured in the "InCytes" section of American Society of Cell Biology Newsletter and nominated for paper of the year in the journal Molecular Biology of the Cell)
Last Updated: 7/21/21