Copper dependent defects in mitochondria
Type of DegreeMaster's Thesis
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Wilson disease (WD) is a disease characterized by excessive copper accumulation in the liver and various other organs. In WD copper is absorbed through dietary consumption and not properly excreted from the body. Excessive accumulation of copper leads to many negative clinical symptoms such as acute liver failure or cirrhosis. The copper accumulation leads to cellular damage and mitochondrial injury. Mitochondria are a direct target of copper ion damage due to mitochondria accumulating copper required for electron transport processes. Though we have identified who, or rather what is affected by excess copper accumulation “why” and “how” remained unanswered. Little is known about the import and export of mitochondrial copper or proteins and mechanisms involved in copper-dependent damage response. Described in this study are two copper-dependent reactions: the oxidation of cellular and mitochondrial thiols as a result of copper accumulation and a copper-related heme defect in Saccharomyces cerevisiae that is alleviated upon the deletion of MRS3. Protein thiols are biologically significant and contribute to stable tertiary and quaternary protein structures. Oxidation of the thiol groups can lead to modulation of protein structure and subsequent negative impacts on protein function. Unbound copper ions are thought to damage protein thiols by causing the emergence of reactive oxygen species (ROS). These ROS can damage the mitochondria by causing structural damage and by inhibiting biochemical reactions. Herein we explore and demonstrate copper-dependent damage that occurs in the cell due to sulfhydryl groups and observe a dose-dependent decrease in total cellular thiols. Heme is a critical iron cofactor in aerobic life that is synthesized primarily in mitochondria. Disturbed heme metabolism causes mitochondrial decay, oxidative stress, and iron accumulation. However, before now there has not been a correlation drawn between imbalanced copper homeostasis and disrupted heme synthesis. A dose-dependent heme defect in response to elevated exogenous copper was observed in yeast and this defect was alleviated by the deletion of MRS3. Taking this into account, the data presented does further solidify a role for iron transporter MRS3 in copper import into mitochondrial matrix plus heme biosynthesis. The transport of both copper and iron by MRS3 can lead to competition in high copper levels that results in alternative transport of iron meaning it is not being transported directly to the heme biogenesis proteins that are in a complex with Mrs3 thus disrupting heme biogenesis. Copper-dependent defects in mitochondria prove to be an area that needs further investigation. Outlining these defects can help to identify more potential pathways and proteins involved in copper homeostasis to better understand mitochondrial metal metabolism.