962A Poster - 15. Models of human disease
Thursday April 07, 2:00 PM - 4:00 PM

Authors:
Ekaterina Migunova ¹; Stefania Bonanni ¹; Megan Kurz ¹; Alessia Vata ¹; Hongwu Liang ²; Fei Wang ²; Chao Zhou ²; Edward Dubrovsky ¹

Affiliations:
1) Fordham University, Bronx, NY; 2) Washington University, St Louis, MO

Keywords:
j. cardiovascular disease; h. mitochondria

Cardiomyopathy (CM) is a disease of heart muscle leading to changes in heart wall morphology, reduced heart contractility and obstruction of blood flow. It affects people of all ages; the adult form of CM is often secondary to systemic causes such as inflammation, malnutrition and other conditions, while infantile CM occurs due to inherited mutations. Mutations of ELAC2/RNaseZ gene, which encodes RNaseZ enzyme, lead to an especially aggressive form of HCM with early onset of symptoms and lethal outcome within one year after birth. RNaseZ is a highly conserved vital enzyme with homologs in all eukaryotes. It is essential for tRNA maturation and therefore for protein synthesis. It has a dual role within a cell, as it is the only enzyme that processes 3’-ends of pre-tRNA in both nucleus and mitochondria.
Previously we have generated a novel fly model of RNaseZ linked CM and demonstrated that it mimics the human disease in all major symptoms. Further investigation of the underlying mechanisms leading to RNaseZ linked abnormal heart morphology is challenged by the dual role of RNaseZ within a cell.
Here we report the effect of CM-linked RNaseZ mutations on mitochondria function. We have found that RNaseZ mutations cause a decrease in mitochondrial complex I activity, which leads to a reduction in mitochondrial ATP synthesis rates. We also have separated the nuclear and mitochondrial roles of RNaseZ to investigate the contribution of each towards the CM phenotype. We have discovered that mutating only mitochondrial RNaseZ is sufficient to cause changes in heart morphology. Lastly, we investigated whether the heart damage originating from RNaseZ dysfunction in mitochondria is cardiac specific or if it is secondary to a systemic disorder, and found that the cardiac damage associated with mutant mitochondrial RNaseZ is heart specific. Overall, these findings improve our understanding of the cellular processes contributing to RNaseZ linked CM.