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theses

Mitochondria are essential organelles for eukaryotic cells, particularly for neurons, which have high-energy demands and do not store glycolytic reserves. Instead, neurons rely on mitochondrial oxidative phosphorylation to meet their energy demands. In addition to energy generation, mitochondria also mediate processes as diverse as sugar and fatty acid breakdown, steroid and lipid synthesis, calcium homeostasis, and apoptosis. Given the critical role of mitochondria in cellular physiology, mitochondrial dysfunction contributes to the etiology of multiple diseases and disorders.
Mitochondrial function is regulated by changes in organelle size, number, and morphology, and these mitochondrial dynamics are the result of the balanced processes of fission/fusion and mitophagy. In addition, mitochondria interact with various motor and adaptor proteins for mitochondrial transport within the cell, which is particularly important for meeting the energy needs of distal synapses in neurons. Fission, fusion, mitophagy and transport have been found to be fairly conserved across various organisms. Some of the genes that mediate these processes are known, but we do not fully understand how they are regulated, how they are coordinated with each other or how these processes change in response to stress or age. Overall, much remains to be understood with respect to mitochondrial dynamics and transport, specifically in neurons.
In the following thesis work I used the model organism Caenorhabditis elegans to study mitochondria in neurons. I examined how the dynamics of fusion and fission are affected in response to oxygen deprivation. In addition, I performed a forward genetic screen to identify novel proteins that may play a role or regulate aspects of mitochondrial dynamics and transport in the neuron even under non-stress conditions. Through this screen, I found new alleles of a known player, DRP-1, in the fission pathway. I also identified two novel genes, MTX-2 and UNC-44, that may play a role in the transport of mitochondria out of the cell body. Finally, in collaboration with postdoc Natalia Morsci, I examined how microtubule motors and the fission/fusion machinery work together to regulate mitochondrial dynamics in the C. elegans neuron.
These findings point the fact that although the basic machinery of mitochondrial dynamics and transport is somewhat understood, in the neuron and potentially other types of cells, there are additional genes that play important roles. Understanding more about these biological processes can shine light on disruptions of mitochondrial dynamics and transport that are linked to human health.

ETD_9309

Ph.D.

Includes bibliographical references

by Nathaly Salazar-Vasquez

doi:10.7282/t3-2fy9-rq54

ETD doctoral

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