RT Dissertation/Thesis
T1 Cellular pathophysiology of MELAS syndrome
A1 Povea Cabello, Suleva
K1 Síndrome MELAS
K1 Enfermedades de origen genético
K1 Biología celular
K1 Cultivo celular
AB MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke- like episodes) syndrome is a rare mitochondrial disorder mainly caused by the m.3243A>G mutation in the mitochondrial DNA. This mutation affects mitochondrial proteins translation, causing a defect in the synthesis of mitochondrial respiratory chain components. MELAS patients suffer from a wide variety of symptoms that involve neurodegeneration and there is no curative treatment for the disease.In this thesis, we have studied MELAS syndrome pathophysiology using patient-derived fibroblasts carrying the m.3243A>G mutation. We evaluated several parameters of mitochondrial function, mitochondrial quality control pathways, such as autophagy and mitophagy, and inflammation. Our results show clear phenotypical alterations in MELAS fibroblast, such as decreased mitochondrial bioenergetics, impaired autophagy/mitophagy fluxes and NLRP3 inflammasome activation. Then, we performed a screening of compounds in a yeast model harboring the A14G mutation (equivalent to A3243G). We tested the effect of one of the positive compounds, rosmarinic acid, in MELAS cybrids and patient-derived fibroblasts. Rosmarinic acid was demonstrated to have a moderate effect on MELAS cellular pathophysiology.However, cybrids and fibroblasts are not much vulnerable to energy- dependent defects resulting from mitochondrial dysfunction. For that reason, we generated induced neurons (iNs) by direct reprogramming of fibroblasts carrying the m.3243A>G mutation. The pathophysiological characterization of MELAS iNs indicates that they can be used as a cellular model to elucidate the mechanisms underlying the disease as well as a possible screening platform.
YR 2023
FD 2023
LK http://hdl.handle.net/10433/16725
UL http://hdl.handle.net/10433/16725
LA en
NO Programa de Doctorado en Biotecnología, Ingeniería y Tecnología Química
NO Línea de Investigación: Biología Celular, Molecular e Ingeniería Genética
NO Clave Programa: DBI
NO Código Línea: 108
NO Universidad Pablo de Olavide de Sevilla. Departamento de Fisiología, Anatomía y Biología Celular
DS RIO
RD May 9, 2026