Deficiency of DNAJC19 Leads to Upregulation of Cellular Stress Responses

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.