Analysis of Mitochondrial Morphology and Function

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DESCRIPTION (provided by applicant): Mitochondria are dynamic organelles that are required for a variety of cellular functions including the production of ATP, apoptosis, lipid biosynthesis, the degradation of environmental toxins, and calcium homeostasis. Alteration to mitochondrial morphology and function has been associated with several human myopathies and neuropathies including Parkinson's, Kearns-Sayre syndrome and Amyotrophic Lateral Sclerosis. In a genetic screen of ~700 late larval/pupal lethal chromosomes, we have identified nine new genes that are required for proper mitochondrial morphology in the Drosophila visceral muscles. One of these new mitochondrial morphology genes is an essential gene: messy mitochondria. Besides its mitochondrial morphology phenotypes, mutations in messy mitochondria express a small/abnormal imaginal disc phenotype, defects in the movement of food along the alimentary canal and an extended larval period. Imaginal discs from larvae homozygous for a null messy mitochondria mutation have disrupted apical/basal polarity. We have mapped Messy mitochondria to the 96B4-B11 on the third chromosome and we have identified a molecular lesion associated with messy mitochondria in the Oxysterol binding protein gene. Oxysterols are intermediates in cholesterol degradation/biosynthetic pathways and have been implicated in a number of human diseases including Arthrosclerosis and Alzheimer's disease and are believed to be involved in a number of important signaling and biosynthetic pathways. Oxysterol binding proteins are a large family of well conserved proteins that are involved in a number of cellular processes including lipid transport, cell polarity, lipid biosynthesis and vesicle transport. The goal of this grant is to characterize the biochemical and cellular requirement for the messy mitochondria gene. This grant will be the first reported genetic characterization of an Oxysterol binding protein in a multicellular genetic organism. Given the interesting phenotypes associated with the messy mitochondria /Oxysterol binding protein gene, we expect that the results will be important for understanding mitochondrial morphology and other cellular processes involving Oxysterols and cholesterol. The goal of this project it to gain a better understanding of the fundamental role that mitochondrial morphology and function has in the cellular processes associated with a variety of human disorders including ALS, Parkinson's disease and MELAS. As AREA grant, this project has been designed to accommodate the training and education of undergraduate researchers.