Sco1 mouse models of human disease: a tool to investigate the role of mitochondria in the regulation of copper homeostasis
Baker, Zakery N 1990-
Copper is a vital micronutrient that impacts a variety of essential biochemical pathways within mammalian cells. Yet little is known about the homeostatic mechanisms that maintain intracellular copper levels or their relative importance across cell types. Recent evidence argues that copper handling pathways contained within the mitochondrion play an active role in the regulation of cellular copper homeostasis, as human patients with pathogenic mutations in the mitochondrial copper chaperone SCO1 exhibit tissue-specific deficits that are attributable in part to a severe copper deficiency. However, how the activity of mitochondrial copper handling pathways is functionally coupled to other cellular copper handling machinery and how this coupling impinges upon cellular copper sensing in general remains ill-defined. Developing an understanding of how the organelle is integrated into the functional framework that regulates copper homeostasis may be further challenged by the fact SCO1 patients from three unique pedigrees present with drastically different, tissue-specific clinical phenotypes, suggesting that mitochondrial signalling through SCO1 to regulate copper homeostasis may exhibit cell type-specific features. To begin investigating these questions, we generated and characterized multiple transgenic Sco1 models of human disease in which SCO1 function is perturbed in the heart and liver, two of the most affected tissues in SCO1 patients. Deletion of Sco1 in the liver was lethal and mice presented with a significant hepatopathy and hepatic steatosis. Sco1 null hepatocytes had both an isolated COX deficiency as well as a severe copper deficiency, the latter of which was attributable to an increase in the degradation of the high-affinity copper transporter CTR1. Deletion of Sco1 in the heart or striated muscle was also lethal with mice developing a dilated cardiomyopathy. Similar to the Sco1 null livers, Sco1 null hearts displayed a combined COX and copper deficiency; however, in the case of the Sco1 null hearts, the copper deficiency was caused by the relocalization of CTR1 to intracellular vesicles rather than its degradation. To further examine the human condition, we also generated Sco1 knock-in mice harbouring a G115S substitution, which in patients causes a fatal infantile hypertrophic cardiomyopathy. The heart of this knock-in mouse phenocopied the Sco1 knockout heart, suggesting that both the null and knock-in models afforded one with the opportunity to investigate the underlying etiology of the associated human diseases. Collectively, my Ph.D. thesis data confirm that SCO1 fulfills an evolutionarily conserved role in maintaining cellular copper homeostasis and identify a novel role for the protein in regulating the function of the copper import machinery.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorLeary, Scot C
CommitteeStone, Scot J; Roesler, William J; Dmitriev, Oleg Y; Unniappan, Suraj
Copyright DateMarch 2018
Cytochrome c Oxidase