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

Abstract

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 ␤-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, BPAmediated 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.

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

“…Autophagy may play an important role in the development of NSCs under physiological condition . NSCs differentiation fate was dependent on specific pathology as well as autophagic conditions and even on different concentration of Mel . Here, we found that HG triggered early differentiation of NSCs into neurons and astrocytes, whereas Mel effectively opposed HG‐mediated differentiation, especially neurogenesis.…”

Bisphenol A aggravates renal ischemia–reperfusion injury by disrupting mitochondrial homeostasis and N‐acetylcysteine mitigates the injurious outcomes

“…This suggestion was in accordance with several previous studies relating to the antioxidant benefit of NAC. A recent study showing the inhibition of ROS generation by NAC significantly reduced DRP1 levels in BPA treated NSC‐derived neuron cultures . NAC has also been shown to enhance the complex I activity of the electron transport chain in an in vitro study using synaptic mitochondria isolated from old mice through the protection of protein sulfhydryl groups of this enzyme complex from the inhibitory effect of increased reactive oxygen species .…”

“…Investigations both in vitro and in vivo have reported that BPA was able to disrupt electron transport chain, decrease ATP synthesis, increase ROS production with subsequent oxidative injury, impair mitochondrial ultrastructure, induce permeability transition, and release proteins that lead to activation of apoptosis . Regarding the role of BPA on mitochondrial homeostasis, recent evidence has shown that chronic BPA exposure impaired mitochondrial dynamics, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells . All these effects of BPA may cause the mitochondria of the BPA‐exposed group to be more easily affected by ischemia–reperfusion than those exposed to the vehicle.…”

“…34 Regarding the role of BPA on mitochondrial homeostasis, recent evidence has shown that chronic BPA exposure impaired mitochondrial dynamics, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells. 36 All these effects of BPA may cause the mitochondria of the BPA-exposed group to be more easily affected by ischemia-reperfusion than those exposed to the vehicle.…”

“…A recent study showing the inhibition of ROS generation by NAC significantly reduced DRP1 levels in BPA treated NSC-derived neuron cultures. 36 NAC has also been shown to enhance the complex I activity of the electron transport chain in an in vitro study using synaptic mitochondria isolated from old mice through the protection of protein sulfhydryl groups of this enzyme complex from the inhibitory effect of increased reactive oxygen species. 38 A role for NAC to protect acetaminophen inhibition of hepatic mitochondrial complex I activity 39 as well as age-related decline of oxidative phosphorylation in mice liver mitochondria has also been shown.…”