Deficiency of DNAJC19 Leads to Upregulation of Cellular Stress Responses

Wachoski-Dark, Emily Mary Ann

Deficiency of DNAJC19 Leads to Upregulation of Cellular Stress Responses

dc.contributor.advisor	Greenway, Steven
dc.contributor.author	Wachoski-Dark, Emily Mary Ann
dc.contributor.committeemember	Shutt, Timothy
dc.contributor.committeemember	Braun, Janice
dc.date	2023-11
dc.date.accessioned	2023-05-23T20:51:56Z
dc.date.available	2023-05-23T20:51:56Z
dc.date.issued	2023-05-11
dc.description.abstract	The dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare autosomal recessive mitochondrial disease that results from mutations in the poorly characterized DNAJC19 gene and is frequently associated with premature death in children. DNAJC19 is a component of the TIM23 complex which imports proteins into mitochondria but has also been implicated in cardiolipin maturation. Better understanding of the role of DNAJC19 will provide insight into the mechanism of disease. Since previous work did not identify abnormalities in cardiolipin content within patient cells, I hypothesized that deficiency of DNAJC19 would negatively impact mitochondrial protein homeostasis. To address my hypothesis, I quantified the impact of DNAJC19 deficiency on the proteome of DCMA patient dermal fibroblasts. I identified an increase in mitochondrial fission, confirming previous observations. Pathway analysis predicted an upregulation of eukaryotic translation initiation factor 2 (EIF2) signaling in patient cells, indicating increased cellular stress. I identified significant increases in gene expression for key genes involved in the integrated stress response (ISR) and the mitochondrial unfolded protein response (UPRmt). Activation of these stress responses was not accompanied by increases in apoptosis, potentially indicating that patient cells can mitigate the cellular stress they face. I then tested two potential therapeutics: SS-31, which reduces oxidative stress, and tauroursodeoxycholic acid (TUDCA), which refolds proteins in the cytosol. Both compounds prevented upregulation of the ISR and the UPRmt. In conclusion, I have identified a novel upregulation of two key cellular stress response pathways in DCMA patient fibroblasts. This work also identified TUDCA as a potentially novel treatment for DCMA and supports the classification of DCMA as a disease of mitochondrial proteostasis.
dc.identifier.citation	Wachoski-Dark, E. M. A. (2023). Deficiency of DNAJC19 leads to upregulation of cellular stress responses (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/116568
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/dspace/41411
dc.language.iso	en
dc.publisher.faculty	Cumming School of Medicine
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Mitochondria
dc.subject	Cellular stress response
dc.subject	Disease mechanism
dc.subject	Integrated stress response
dc.subject	Unfolded protein response
dc.subject	DCMA
dc.subject.classification	Biology--Cell
dc.subject.classification	Microbiology
dc.title	Deficiency of DNAJC19 Leads to Upregulation of Cellular Stress Responses
dc.type	master thesis
thesis.degree.discipline	Medicine – Cardiovascular/Respiratory Science
thesis.degree.grantor	University of Calgary
thesis.degree.name	Master of Science (MSc)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.