Why do allelic variants of the mitochondrial chaperone SCO1 cause clinically heterogeneous forms of disease? A mouse model and proximity ligation study

SCO1 is a ubiquitously expressed, nuclear-encoded mitochondrial protein that has an essential role in cytochrome c oxidase (COX) assembly and the regulation of cellular copper homeostasis. While SCO1 mutations result in clinically heterogenous forms of disease with fatal, neonatal outcomes, it remains unclear why allelic variants unique to each SCO1 pedigree primarily affect heart, liver or brain function. I therefore created and phenotyped three whole body Sco1 knockin mouse models harbouring one or two alleles of the murine equivalent of the pathogenic SCO1 P174L, SCO1 G132S and SCO1 M294V alleles, and characterized the wild-type and mutant SCO1 interactomes in a human cell culture model to identify mechanisms underlying the observed clinical heterogeneity. Sco1 knockin mice were indistinguishable from their wild-type littermates and, unlike SCO1 patients, did not exhibit an outward failure to thrive. Biochemical, molecular and elemental tissue analyses revealed that the murine heart was most susceptible to loss of SCO1 function. However, Sco1 M227V brains exhibited a significant, combined COX and copper deficiency mirroring the encephalopathy observed in the relevant human SCO1 pedigree. These findings strongly suggest that in general the heart is most vulnerable to loss of SCO1 function in an isogenic background, and single nucleotide polymorphisms at modifier loci are likely to contribute significantly to the clinical heterogeneity observed across SCO1 pedigrees. My SCO1 interactome studies identified several interesting candidate partners whose interactions may be perturbed by pathogenic SCO1 variants and contribute to tissue-specific clinical phenotypes. I prioritized characterizing the importance of the SCO1-COX16 interaction to CuA site maturation, given that its abundance was greatly reduced in some brain regions and its affinity for SCO1 was attenuated by the M294V substitution. Consistent with these findings, I found that COX16 overexpression was able to partially complement the COX deficiency in SCO1 patient fibroblasts harbouring the P174L allele but not the M294V allele. Collectively, my PhD thesis studies emphasize the importance of genetic heterogeneity in determining clinical outcomes in different SCO1 pedigrees, and highlight the unique effect of each pathogenic variant on the composition of the SCO1 interactome and its affinity for various partners.

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Saskatchewan

Year dc:date.issued

2025

Author dc:creator

• Ghosh, Sampurna

Committee members dc:contributor.committeemember

• Stone, Scot J
• Roesler, Bill
• Dmitriev, Oleg
• Coakwell, Mika Asai
• Shoubridge, Eric A
• Wu, Michael

• SCO1 mutations
• cytochrome c oxidase
• COX deficiency
• clinical heterogeneity
• BioID
• knock-in mice
• copper deficiency
• interactome
• tissue specificity

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10388/16925

OAI identifier oai:identifier

oai:harvest.usask.ca:10388/16925