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      MeHg Causes Ultrastructural Changes in Mitochondria and Autophagy in the Spinal Cord Cells of Chicken Embryo

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      1 , , 2 , 2
      Journal of Toxicology
      Hindawi

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          Abstract

          Methylmercury (MeHg) is a known neurodevelopmental toxicant, which causes changes in various structures of the central nervous system (CNS). However, ultrastructural studies of its effects on the developing CNS are still scarce. Here, we investigated the effect of MeHg on the ultrastructure of the cells in spinal cord layers. Chicken embryos at E3 were treated in ovo with 0.1 μg MeHg/50 μL saline solution and analyzed at E10. Then, we used transmission electron microscopy (TEM) to identify possible damage caused by MeHg to the structures and organelles of the spinal cord cells. After MeHg treatment, we observed, in the spinal cord mantle layer, a significant number of altered mitochondria with external membrane disruptions, crest disorganization, swelling in the mitochondrial matrix, and vacuole formation between the internal and external mitochondrial membranes. We also observed dilations in the Golgi complex and endoplasmic reticulum cisterns and the appearance of myelin-like cytoplasmic inclusions. We observed no difference in the total mitochondria number between the control and MeHg-treated groups. However, the MeHg-treated embryos showed an increased number of altered mitochondria and a decreased number of mitochondrial fusion profiles. Additionally, unusual mitochondrial shapes were found in MeHg-treated embryos as well as autophagic vacuoles similar to mitophagic profiles. In addition, we observed autophagic vacuoles with amorphous, homogeneous, and electron-dense contents, similar to the autophagy. Our results showed, for the first time, the neurotoxic effect of MeHg on the ultrastructure of the developing spinal cord. Using TEM we demonstrate that changes in the endomembrane system, mitochondrial damage, disturbance in mitochondrial dynamics, and increase in mitophagy were caused by MeHg exposure.

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          A series of normal stages in the development of the chick embryo

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            Autophagy in cell death: an innocent convict?

            The visualization of autophagosomes in dying cells has led to the belief that autophagy is a nonapoptotic form of programmed cell death. This concept has now been evaluated using cells and organisms deficient in autophagy genes. Most evidence indicates that, at least in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. This review summarizes the evidence linking autophagy to cell survival and cell death, the complex interplay between autophagy and apoptosis pathways, and the role of autophagy-dependent survival and death pathways in clinical diseases.
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              Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis.

              OPA1 encodes a large GTPase related to dynamins, anchored to the mitochondrial cristae inner membrane, facing the intermembrane space. OPA1 haplo-insufficiency is responsible for the most common form of autosomal dominant optic atrophy (ADOA, MIM165500), a neuropathy resulting from degeneration of the retinal ganglion cells and optic nerve atrophy. Here we show that down-regulation of OPA1 in HeLa cells using specific small interfering RNA (siRNA) leads to fragmentation of the mitochondrial network concomitantly to the dissipation of the mitochondrial membrane potential and to a drastic disorganization of the cristae. These events are followed by cytochrome c release and caspase-dependent apoptotic nuclear events. Similarly, in NIH-OVCAR-3 cells, the OPA1 siRNA induces mitochondrial fragmentation and apoptosis, the latter being inhibited by Bcl2 overexpression. These results suggest that OPA1 is a major organizer of the mitochondrial inner membrane from which the maintenance of the cristae integrity depends. As loss of OPA1 commits cells to apoptosis without any other stimulus, we propose that OPA1 is involved in the cytochrome c sequestration and might be a target for mitochondrial apoptotic effectors. Our results also suggest that abnormal apoptosis is a possible pathophysiological process leading to the retinal ganglion cells degeneration in ADOA patients.
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                Author and article information

                Contributors
                Journal
                J Toxicol
                J Toxicol
                JT
                Journal of Toxicology
                Hindawi
                1687-8191
                1687-8205
                2018
                28 August 2018
                : 2018
                : 8460490
                Affiliations
                1Instituto de Ciências Naturais Humanas e Sociais, UFMT, Avenida Alexandre Ferronato 1200, Setor Industrial, Sinop, MT 78557287, Brazil
                2Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, UFSC, Campus Universitário, Trindade, Florianópolis, SC 88040-900, Brazil
                Author notes

                Academic Editor: Brad Upham

                Author information
                http://orcid.org/0000-0003-1409-3044
                http://orcid.org/0000-0002-3635-0526
                Article
                10.1155/2018/8460490
                6136469
                f993fdb0-109a-449f-acc3-61f9fbdd3b70
                Copyright © 2018 Fabiana F. Ferreira et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 June 2018
                : 6 August 2018
                Categories
                Research Article

                Toxicology
                Toxicology

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