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Investigation of the mechanisms of toxicity in methylmalonic academia - evaluation of cell bioenergetics, oxidative stress, signaling pathways and potential strategies of protection

Abstract

Disorders in the metabolism of carboxylic acid inherited diseases relatively common in hospitalized children, with a prevalence of 1: 1,000 newborns. Affected patients accumulate specific organic acids in their tissues and biological fluids and have severe dysfunction mainly in organs highly dependent of energy such as brain and heart. These diseases are caused by severe deficiency or absence of activity of enzymes or transport proteins and comprise organic acidemias and defects of mitochondrial fatty acid oxidation. Without proper treatment, a large number of these patients have fatal outcome in the first year of life, while those who survive the early stages have a varying degree of sequels. Considering that the pathogenesis of tissue damage in these diseases is poorly understood, the goal of this project is, by assessing the energy metabolism and redox homeostasis, which are systems fundamental for development and cell function, in neural cells lines, 1) to investigate neurotoxic effects of the accumulating compounds in methylmalonic acidemia alone or in situation of hyperammonemia; and 2) to develop a knockout cellular model of this disease by silencing the expression of the enzyme involved in this metabolic pathway. We intend, therefore, to contribute to the understanding of the cellular and molecular bases in theis condition, and to determine possible therapeutic targets, proposing protection strategies based on the elucidation of the pathogenic mechanisms of cell degeneration in this pathology. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NERES-SANTOS, RAQUEL SILVA; JUNHO, CAROLINA VICTORIA CRUZ; PANICO, KARINE; CAIO-SILVA, WELLINGTON; PIERETTI, JOANA CLAUDIO; TAMASHIRO, JULIANA ALMEIDA; SEABRA, AMEDEA BAROZZI; RIBEIRO, CESAR AUGUSTO JOAO; CARNEIRO-RAMOS, MARCELA SORELLI. Mitochondrial Dysfunction in Cardiorenal Syndrome 3: Renocardiac Effect of Vitamin C. CELLS, v. 10, n. 11 NOV 2021. Web of Science Citations: 0.
DA COSTA, RENATA T.; DOS SANTOS, MARCELLA B.; SILVA, IZABEL C. S.; DE ALMEIDA, RAQUEL P.; TERUEL, MARCELA S.; CARRETTIERO, DANIEL C.; RIBEIRO, CESAR A. J. Methylmalonic Acid Compromises Respiration and Reduces the Expression of Differentiation Markers of SH-SY5Y Human Neuroblastoma Cells. ACS Chemical Neuroscience, v. 12, n. 14, p. 2608-2618, JUL 21 2021. Web of Science Citations: 0.
FERRAZ, LETICIA SILVA; DA COSTA, RENATA TORRES; DA COSTA, CLAUDIA ALVES; JOAO RIBEIRO, CESAR AUGUSTO; ARRUDA, DENISE COSTA; MARIA-ENGLER, SILVYA STUCHI; RODRIGUES, TIAGO. Targeting mitochondria in melanoma: Interplay between MAPK signaling pathway and mitochondrial dynamics. Biochemical Pharmacology, v. 178, AUG 2020. Web of Science Citations: 0.

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