Deficiency of DNAJC19 Leads to Upregulation of Cellular Stress Responses

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

Mitochondrial Protein Homeostasis and Cardiomyopathy

Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial cardiomyopathies are related to defects in the maintenance of mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known mitochondrial diseases that have been associated with cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ heat shock protein family member C19 (DNAJC19), mitochondrial import inner membrane translocase subunit TIM16 (MAGMAS), translocase of the inner mitochondrial membrane 50 (TIMM50), mitochondrial intermediate peptidase (MIPEP), X-prolyl-aminopeptidase 3 (XPNPEP3), HtraA serine peptidase 2 (HTRA2), caseinolytic mitochondrial peptidase chaperone subunit B (CLPB) and heat shock 60-kD protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential therapeutics