Shutt, TimothyKhan, AnealZhao, Tian Rui2023-10-042023-10-042023-09-22Zhao, T. R. (2023). Mitochondrial skeletal disorders provide insight into the effect of mitchondrial proteostatic stress on steroidogenesis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.https://hdl.handle.net/1880/117271https://doi.org/10.11575/PRISM/42113Mitochondria are best known for their role in energy production, and impairments in this essential function are generally thought to cause mitochondrial disease, which typically affects organs and tissues with high energy demand. However, increasing evidence shows that impairments to other critical mitochondrial functions such as lipid metabolism, and steroidogenesis can also contribute to mitochondrial diseases. In this thesis, we identified a group of mitochondrial diseases where mitochondrial protein homeostasis is disrupted, which we termed mitochondrial skeletal disorders, as the patients exhibited phenotypes such as skeletal dysplasia, short stature, and cataracts. In addition, further investigation identified a potential mechanism by which altered mitochondrial protein homeostasis and increased steroidogenesis may contribute to these patient phenotypes. First, we identified novel pathogenic variants in phosphatidylserine decarboxylase (PISD) gene from patients with short stature, neurodevelopmental issues, and cataracts. We demonstrated that the variants impair function and stability of PISD and are likely causative of their disease. We also identified evidence for impaired activity of inner mitochondrial membrane (IMM) proteases, suggesting dysfunctions in mitochondrial protein homeostasis. To further investigate the mechanism by which impaired mitochondrial proteostasis may lead to these phenotypes, we tested the hypothesis that impaired mitochondrial proteostasis can lead to overproduction of the stress hormone cortisol, as this could potentially explain the patients’ phenotypes described above. Using both pharmacological and genetic stresses to impair mitochondrial proteostasis, we showed impaired mitochondrial protein import activates STARD1, a mitochondrial protein crucial in steroidogenesis. We then showed that increased cortisol production is STARD1 dependent and follows a biphasic response to mitochondrial stress. Overall, these findings expand our current understanding of mitochondrial disease and link mitochondrial quality control and steroidogenesis as potential disease mechanisms.enUniversity 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.mitochondriamitochondrial diseasesPISDSTARD1LONP1steroidogenesismitochondrial skeletal disordersmitochondrial protein homeostasisstressGeneticsBiology--MolecularBiochemistrydoctoral thesis