Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation.

Autor:	Agarwal S; From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and., Yadav A; From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and., Tiwari SK; From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and., Seth B; From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and., Chauhan LK; the Central Instrumentation Facility, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India., Khare P; From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and., Ray RS; the Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group., Chaturvedi RK; From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group and the Academy of Scientific and Innovative Research and rajnish@iitr.res.in itrcrajnish@gmail.com.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2016 Jul 29; Vol. 291 (31), pp. 15923-39. Date of Electronic Publication: 2016 Jun 01.
DOI:	10.1074/jbc.M115.709493
Abstrakt:	The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU- and β-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPA-mediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus. (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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