RESUMO
The causes of neurodegenerative diseases are complex with likely contributions from genetic susceptibility and environmental exposures over an organism's lifetime. In this review, we examine the role that aquatic models, especially zebrafish, have played in the elucidation of mechanisms of heavy metal toxicity and nervous system function over the last decade. Focus is applied to cadmium, lead, and mercury as significant contributors to central nervous system morbidity, and the application of numerous transgenic zebrafish expressing fluorescent reporters in specific neuronal populations or brain regions enabling high-resolution neurodevelopmental and neurotoxicology research.
Assuntos
Intoxicação do Sistema Nervoso por Metais Pesados/etiologia , Metais Pesados/toxicidade , Degeneração Neural , Sistema Nervoso/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Metais Pesados/genética , Intoxicação do Sistema Nervoso por Metais Pesados/metabolismo , Intoxicação do Sistema Nervoso por Metais Pesados/patologia , Humanos , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Sistema Nervoso/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Medição de Risco , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
The cellular energy metabolism shift, characterized by the inhibition of oxidative phosphorylation (OXPHOS) and enhancement of glycolysis, is involved in nickel-induced neurotoxicity. MicroRNA-210 (miR-210) is regulated by hypoxia-inducible transcription factor-1α (HIF-1α) under hypoxic conditions and controls mitochondrial energy metabolism by repressing the iron-sulfur cluster assembly protein (ISCU1/2). ISCU1/2 facilitates the assembly of iron-sulfur clusters (ISCs), the prosthetic groups that are critical for mitochondrial oxidation-reduction reactions. This study aimed to investigate whether miR-210 modulates alterations in energy metabolism after nickel exposure through suppressing ISCU1/2 and inactivating ISCs-containing metabolic enzymes. We determined that NiCl2 exposure leads to a significant accumulation of HIF-1α, rather than HIF-1ß, in Neuro-2a cells. The miR-210 overexpression and ISCU1/2 downregulation was observed in a dose- and time-dependent manner. The gain-of-function and loss-of-dysfunction assays revealed that miR-210 mediated the ISCU1/2 suppression, energy metabolism alterations, and ISC-containing metabolic enzyme inactivation after nickel exposure. In addition, the impact of miR-210 on ISC-containing metabolic enzymes was independent from cellular iron regulation. Overall, these data suggest that repression of miR-210 on ISCU1/2 may contribute to HIF-1α-triggered alterations in energy metabolism after nickel exposure. A better understanding of how nickel impacts cellular energy metabolism may facilitate the elucidation of the mechanisms by which nickel affects the human health.
