Elucidating the Role of RNase Z in Mitochondrial Quality Control in Caenorhabditis Elegans
Held, James Paul
0000-0003-4322-2108
:
2024-06-26
Abstract
Proper mitochondrial function is essential for cell health and homeostasis. To maintain healthy mitochondria, protective mechanisms have evolved that sense mitochondrial stress and ameliorate it. Collectively these pathways are referred to as mitochondrial quality control mechanisms. Elucidating the molecular basis by which these pathways work is one way to better understand mitochondrial homeostasis and, in the process, learn ways to protect against mitochondrial stress associated diseases including many metabolic and neurological disorders. RNase Z is an essential endonuclease required for the processing of nascent tRNAs across eukaryotes. Mutations in RNase Z in humans (encoded by the gene ELAC2) are associated with prostate cancer and hypertrophic cardiomyopathy. How RNase Z mutations cause or exacerbate these diseases is poorly understood. I have identified that RNase Z in the model system Caenorhabditis elegans, plays a crucial role in regulating a conserved mitochondrial quality control pathway called the mitochondrial unfolded protein response (UPRmt). Nuclear localized RNase Z in C. elegans is both necessary and sufficient for UPRmt in the intestine of animals—a major metabolic tissue. Moreover, RNase Z likely regulates UPRmt via altered processing of its RNA substrates. Additionally, by conducting a forward genetic screen, I discovered that a small chain fatty acid metabolism pathway that is responsive to germline status and micronutrient availability can regulate the nuclear localization of RNase Z. Together these findings show for the first time that, in addition to its ‘housekeeping’ role in translation, RNase Z has a specific role in mitochondrial quality control. This work provides novel insight into the molecular basis of mitochondrial quality control and provides an alternative mechanism by which mutations in human ELAC2 may lead to disease outcomes.