| Description |
Mitochondrial movement is a conserved cellular process observed in all eukaryotes, ranging from single-celled organisms to multicellular organisms. The distribution of mitochondria in most eukaryotes is dictated by the subcellular need for adenosine triphosphate (ATP) and intracellular calcium buffering. This is most apparent in polarized eukaryotic cells, like budding yeast and mammalian neurons. Perturbances in mitochondrial movement in polarized cells can impact cell division, function, and even survival. In fact, there are a growing number of neurodegenerative diseases linked to mitochondrial distribution defects. Guanine triphosphatase (GTPase) EF-hand protein of mitochondria or mitochondrial Rho GTPase (Gem1/Miro) proteins are the only known mitochondrial surface receptors implicated in mitochondrial movement. Although Gem1/Miro proteins are conserved from yeast to human, the molecular mechanism for mitochondrial movement is not apparently well conserved. Gem1, the yeast homologue of mammalian Miro, is implicated in actin-based mitochondrial movement. However, to date, there is no clear evidence that it is associated with motor proteins. Interestingly, both Gem1 and Miro are found at mitochondrial-endoplasmic reticulum (ER) contact sites and it is possible that mitochondria are moved by "hitching a ride" with the ER. The first part of this dissertation will focus on a yeast mitochondrial-ER connection and test whether mitochondrial movement in yeast can be mediated through these contact sites. Miro, the mammalian homologue of Gem1, on the other hand, forms a complex with motor proteins to move mitochondria along microtubules. The molecular function of mammalian Miro has been extensively studied in flies and mammalian cell culture. However, our understanding of the cellular and physiological consequences of disrupted mitochondrial motility in mammals is lacking. The latter part of this dissertation will focus on experiments that will test the in vivo function of Miro1 in neuronal maintenance and neurodegeneration. This dissertation will provide a detailed cellular and physiological analysis of Gem1/Miro-mediated mitochondrial movement using two model organisms, Saccharomyces cerevisiae and Mus Musculus. Chapter 2 will show that Gem1 is not required for mitochondrial-ER connections and that mitochondrial movement does not require a specific type of mitochondrial-ER connection found in yeast. Chapter 3 will provide the first direct evidence demonstrating that Miro1 is neuroprotective and that loss of Miro1 in neurons results in neurodegenerative phenotypes similar to human Motor Neuron Disease. |
