Banca de QUALIFICAÇÃO: FAGNER SANT'ANA JANUÁRIO

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
STUDENT : FAGNER SANT'ANA JANUÁRIO
DATE: 04/04/2023
TIME: 14:00
LOCAL: Sala 207 do Bloco Zeta do Campus de São Bernardo do Campo da Universidade Federal do ABC
TITLE:

INVESTIGATION OF THE EFFECTS OF PROPIONIC ACID ON BIOENERGETIC AND CELLULAR OXIDATIVE STRESS IN A HUMAN OLIGODENDROCYTE LINE

PAGES: 75
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUBÁREA: Metabolismo e Bioenergética
SUMMARY:

Propionic acidemia is one of the most prevalent autosomal recessive metabolic disorders, with an estimated incidence of 1:50,000 in patients, caused by a deficiency in the activity of the enzyme propionyl-CoA carboxylase. Enzyme blockade leads to accumulation of propionyl-CoA and the metabolites propionic acid (PA), 3-hydroxypropionic acid, methylcitric acid, and propionylglycine, as well as ammonia and lactate, in patient tissues and body fluids, especially during metabolic crises. It should be emphasized that the neuropathological findings present in affected patients include demyelination with cerebral atrophy and abnormalities of the putamen and caudate nuclei. Thus, the present study investigated the effects of PA on a human oligodendrocyte cell lineage, since oligodendrocytes are responsible for the formation of the myelin sheath in the central nervous system (CNS) and patients present marked demyelination. For that, cells of the MO3.13 lineage, cultivated in DMEM supplemented with 10% FBS, were exposed to PA in concentrations ranging from 0.1 to 10.0 mM, whereas the control group did not contain the acid, for different time intervals (6 to 72 hours). At the end of the exposure times, metabolic viability, glucose consumption, GSH antioxidant content and the production of reactive species with the dichlorofluorescein probe (DCFH) were evaluated. The results showed that PA significantly reduced metabolic viability after 12, 24, 48 and 72 hours of exposure. Changes in cell morphology were also observed after exposure to PA for 24 hours at concentrations of 5 and 10 mM. Furthermore, exposure to PA (10 mM) for 24 hours significantly reduced the number of cells, determined by counting nuclei stained with Hoechst 33342 dye. A significant increase in the release of the enzyme lactate dehydrogenase into the culture medium was also observed, suggesting that PA compromises cell membrane. Exposure of cells to PA for 6 hours did not change glucose consumption. However, a significant increase in this parameter was observed in cells exposed to PA for 12 hours. A significant reduction in the intracellular content of the antioxidant GSH was also observed after 12 hours of exposure to PA, with no changes observed at 6, 24 and 48 hours. Furthermore, no significant changes were found in DCFH oxidation in cells exposed to PA for 24 and 48 hours. The ability of bezafibrate (200 nM) and melatonin (1 µM and 1 mM) to prevent or reverse the toxic effects of PA on metabolic viability was also evaluated. However, no protective effect was observed. Finally, the effects of PA on metabolic viability in undifferentiated and retinoic acid-differentiated SH-SY5Y neuroblastoma cell lines were also studied. It was observed that PA also significantly reduced the viability of SH-SY5Y cells in a concentration and time dependent manner. This study demonstrated for the first time the deleterious effects of PA metabolic viability and GSH content on human oligodendrocytes, suggesting that the accumulation of this metabolite may be related to the changes in white matter observed in patients. Finally, as propionic acidemia is a developmental disease, early defects in maturation and myelination may further clarify its pathophysiology; especially in the neonatal and early childhood periods.

COMMITTEE MEMBERS:
Presidente - Interno ao Programa - 1227329 - CESAR AUGUSTO JOAO RIBEIRO
Membro Titular - Examinador(a) Interno ao Programa - 1887027 - FERNANDO AUGUSTO DE OLIVEIRA RIBEIRO
Membro Titular - Examinador(a) Externo ao Programa - 1669152 - DANIEL CARNEIRO CARRETTIERO
Membro Suplente - Examinador(a) Interno ao Programa - 2605490 - SERGIO DAISHI SASAKI
Membro Suplente - Examinador(a) Externo ao Programa - 1831780 - DANILO DA CRUZ CENTENO