Mitochondrial Dynamics in Eukaryotic Cells

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, as 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.  Genetic, cellular and biochemical studies from our lab reveal that 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 that encircle the outer mitochondrial membrane and ‘clip’ mitochondrial tubules into smaller pieces.  Two additional molecules, called Fis1p and Mdv1p, work together with Dnm1p during the fission reaction. We recently defined sequential steps in the assembly of functional fission complexes containing all three proteins.  Our current goal is to determine how conformational changes in this structure, and the Dnm1p GTPase cycle, lead to outer membrane scission. We are also interested in the molecular machinery that carries out inner mitochondrial membrane division. Ultimately, these two structures must “converse” to ensure that inner and outer membrane division are coordinated.

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 including dominant optic atrophy and Charcot-Marie-Tooth Syndrome.  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 and Inheritance

Mitochondria are essential organelles that cannot be generated de novo. Thus, transport of mitochondria from the mother to the newly formed daughter cell is an essential part of cell division. Work from our lab indicates that the Miro family of GTPases plays an important role in mitochondrial inheritance during division. The yeast Miro homolog, called 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. Studies from our lab reveal that Gem1p acts in one of three pathways that promote mitochondrial inheritance during cell division.

Recent studies suggest that mammalian and insect homologs of Gem1p recruit molecular motors that transport mitochondria along cytoskeletal tracks. In budding yeast, however, mitochondrial movement occurs on actin filaments rather than on microtubules. Thus, attachment of mitochondria to microtubule motors is unlikely to be the conserved function of Gem1p. We are currently studying how Gem1p controls mitochondrial movement on different cytoskeletal elements in eukaryotes.