Graduation Date

Fall 12-16-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Howard S. Fox

Second Advisor

Kelly L. Stauch

Abstract

Mitochondria are at the center of biological phenomena such as aging and diseases, especially neurodegenerative diseases. While the discovery of mitochondria only came approximately 200 years after the cell was discovered, a lot of progress has been made since. The mitochondrial genome encodes proteins vital for mitochondrial function. These proteins are only a subset of the proteins present in mitochondria; the rest are nuclear encoded. The nucleus also encodes cytosolic proteins vital for mitochondrial maintenance. One of these is Parkin, an E3 ubiquitin ligase that ubiquitinates mitochondrial proteins as mitochondria become depolarized. Its activity has been shown to be involved in mitochondrial autophagy (mitophagy). Mitophagy occurs as mitochondria become damaged. Mutation-accumulation is a form of damage, and it is unknown if mitophagy is triggered in response to mutation-accumulation in the mitochondrial genome. To understand diseases associated with mitochondrial dysfunction, it is important to answer this question because mitochondrial mutation accumulation is linked to numerous diseases, and as such if Parkin could be utilized as a therapeutic target, many diseases not curable today may become obsolete through this target. Polymerase γ (Polg) is another nuclear-encoded protein, vital for maintenance of the mitochondrial genome by proofreading replication errors in the mitochondrial genome. Genetically engineered proof-reading-deficient Polg mutator mice have previously been created and were utilized in the studies outlined in this dissertation to induce mitochondrial stress so that the feasibility of utilizing Parkin as a therapeutic target may be tested. This dissertation discusses mitochondria from a historical perspective, shows unexpected experimental data on the interplay between the mitochondrial genome and Parkin that show reduction in mutations in the absence of Parkin along with an increase in possibly protective Control Region Multimers (CRMs). We also discuss current challenges in the field of mitochondrial research with a particular focus on the mitochondrial genome, and finally give suggestions for future directions of research based on data and knowledge gained throughout the work and writing of the dissertation.

Comments

2022 Copyright, the authors

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