Browsing by Author "Adrita, Chanda"

MELAS syndrome is a multi-organ disorder with a wide range of clinical manifestations, including hearing loss, cardiomyopathy, retinopathy, and stroke-like events. It can also be associated with type 2 diabetes. Eighty per cent of MELAS Syndrome cases have a 3243A>G mutation in the MTTL1 gene, which codes for tRNA (Leu-UUR). Although the exact cause of MELAS syndrome remains unknown, microvascular angiopathy and endothelial dysfunction, which result in reduced microvascular perfusion, are assumed to have a role in the reported phenotype. Yet, it is unclear how important this depicted angiopathy is in general and how it relates to the disease-specific stroke-like episodes in particular. In this thesis, I employed MELAS-patient-derived human induced pluripotent stem cell (hiPSC)-derived endothelial cells (EC) under flow as a disease model to investigate the possibility of an altered endothelial cell phenotype or function that could account for the disease phenotype. I used hiPSCs from healthy controls and patient-derived iPS-cell lines from MELAS patients with the 3243A>G mutation with different levels of heteroplasmy in all the experiments. Transcriptional patterns reflecting the flow response were observed, demonstrating that the MELAS hiPSC-EC cells respond to a flow stimulus. In the high-heteroplasmy cell lines, there was a significant downregulation of genes related to one carbon folate metabolism and serine biosynthesis, especially in response to flow, and these changes were also indicated in basal conditions. This is interesting as the same metabolic pathways have been shown dysregulated in other mitochondrial diseases. This study showed no appreciable difference in the mitochondrial oxygen respiration rate between MELAS-patient and control hiPSC-EC. These findings could link the disease phenotype to this web of pathways and explain the mechanism underlying the pathophysiology of MELAS syndrome.