Methylmalonic Acid Compromises Respiration and Reduces the Expression of Differentiation Markers of SH-SY5Y Human Neuroblastoma Cells
| Autor: | Renata Torres da Costa, Izabel Cristina Santos Silva, Marcela Simões Teruel, Daniel Carneiro Carrettiero, César Augusto João Ribeiro, Raquel Pascott de Almeida, Marcella Bacelar dos Santos |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
SH-SY5Y Physiology Cognitive Neuroscience Cellular differentiation Enolase Methylmalonic acidemia Methylmalonic acid Biochemistry 03 medical and health sciences chemistry.chemical_compound Neuroblastoma 0302 clinical medicine Internal medicine medicine Humans 030304 developmental biology 0303 health sciences biology Respiration Metabolic disorder Infant Newborn food and beverages Methylmalonyl-CoA Mutase Cell Biology General Medicine medicine.disease Phenotype Antigens Differentiation Endocrinology chemistry Synaptophysin biology.protein 030217 neurology & neurosurgery Methylmalonic Acid |
| Zdroj: | ACS chemical neuroscience. 12(14) |
| ISSN: | 1948-7193 |
| Popis: | Methylmalonic acidemia is a rare metabolic disorder caused by the deficient activity of l-methylmalonyl-CoA mutase or its cofactor 5-deoxyadenosylcobalamin and is characterized by accumulation of methylmalonic acid (MMA) and alternative metabolites. The brain is one of the most affected tissues and neurologic symptoms, characterized by seizures, mental retardation, psychomotor abnormalities, and coma, commonly appear in newborns. The molecular mechanisms of neuropathogenesis in methylmalonic acidemia are still poorly understood, specifically regarding the impairments in neuronal development, maturation, and differentiation. In this study, we investigated the effects of MMA in both undifferentiated and differentiated phenotypes of SH-SY5Y human neuroblastoma cells. We observed an increase in glucose consumption and reduction in respiratory parameters of both undifferentiated and differentiated cells after exposition to MMA, suggesting that differentiated cells are slightly more prone to perturbations in respiratory parameters by MMA than undifferentiated cells. Next, we performed qPCR of mature neuronal-specific gene markers and measured mitochondrial functioning to evaluate the role of MMA during differentiation. Our results showed that MMA impairs the respiratory parameters only at the late stage of differentiation and downregulates the transcriptional gene profile of mature neuronal markers neuron-specific enolase (ENO2) and synaptophysin (SYP). Altogether, our findings point out important changes observed during neuronal maturation and energetic stress vulnerability that can play a role in the neurological clinical symptoms at the newborn period and reveal important molecular mechanisms that could help the screening of targets to new approaches in the therapies of this disease. |
| Databáze: | OpenAIRE |
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