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Prolonged In Vitro Exposure to Methylmalonic Acid Induces Inflammation, Glutamate Metabolism Disruption, and Alters
Rômulo Rodrigo de Souza Almeida1,2, Larissa Daniele Bobermin1,2,3, Izaviany Schmitz1
1Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Abstract:
Methylmalonic acidemia is an inherited neurometabolic disorder characterized by accumulation of methylmalonic acid (MMA) in different tissues, particularly in the brain. As a result, patients frequently exhibit progressive neurological deterioration, accompanied by episodes of acute encephalopathy following metabolic decompensation. Astrocytes are glial cells that maintain the central nervous system homeostasis and may be important cellular targets of MMA-induced dysfunction. However, most in vitro experimental models for the study of methylmalonic acidemia are based on short-term exposure to the toxic metabolites that accumulate in patients. In this study, we used a prolonged experimental model, which has not been yet explored in the context of glial cells, focusing on the inflammatory response, glutamate metabolism, and putative signaling pathways that can contribute to understanding cellular damage observed in methylmalonic acidemia. It is emphasized that MMA is persistently elevated in the brain of the affected patients. Prolonged MMA exposure induced inflammation with significant increase in gene expression of cyclooxygenase 2, interleukin (IL)-1β and its receptor (IL1R1), and IL-6, accompanied by a decrease in IL-10 expression. MMA also increased glutamate uptake and the activity and gene expression of the enzyme glutamine synthetase, while it downregulated glial cell-derived neurotrophic factor (GDNF). The expression of NFκB, p38 MAPK, Nrf2, heme oxygenase 1, PGC-1α, and sirtuin 1 were also modulated by MMA treatment, indicating the critical role of these signaling pathways in the MMA-induced persistent gliotoxicity. Finally, it is conceivable that these changes may significantly contribute to clarify the pathogenesis of methylmalonic acidemia.
Insights
Methylmalonic acidemia causes toxic methylmalonic acid (MMA) buildup in the brain. Prolonged MMA exposure in a new model shows it triggers inflammation and alters glutamate metabolism in glial cells, contributing to disease.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Cellular Biology
Background:
- Methylmalonic acidemia (MMA) is an inherited neurometabolic disorder causing methylmalonic acid accumulation, particularly in the brain.
- This leads to progressive neurological damage and encephalopathy.
- Astrocytes, crucial for CNS homeostasis, are potential targets of MMA toxicity, but models often use short-term exposure.
Purpose of the Study:
- To investigate the effects of prolonged methylmalonic acid (MMA) exposure on glial cells using a novel experimental model.
- To explore MMA's impact on the inflammatory response, glutamate metabolism, and signaling pathways in astrocytes.
- To elucidate the cellular mechanisms underlying MMA-induced gliotoxicity in methylmalonic acidemia.
Main Methods:
- Utilized a prolonged in vitro experimental model with sustained methylmalonic acid (MMA) exposure.
- Analyzed gene expression changes related to inflammation (COX-2, IL-1β, IL-1R1, IL-6, IL-10).
- Assessed glutamate uptake, glutamine synthetase activity and expression, and GDNF levels. Investigated signaling pathways (NFκB, MAPK, Nrf2, etc.).
Main Results:
- Prolonged MMA exposure induced significant inflammation in astrocytes, increasing pro-inflammatory cytokines (IL-1β, IL-6) and decreasing anti-inflammatory IL-10.
- MMA enhanced glutamate uptake and glutamine synthetase activity/expression, while downregulating GDNF.
- Key signaling pathways including NFκB, p38 MAPK, Nrf2, and others were modulated, indicating their role in MMA-induced gliotoxicity.
Conclusions:
- Prolonged MMA exposure in astrocytes triggers inflammatory responses and alters glutamate homeostasis.
- The study highlights the role of specific signaling pathways in MMA-induced gliotoxicity.
- These findings offer insights into the pathogenesis of methylmalonic acidemia and potential therapeutic targets.
