Aluminum-induced defective mitochondrial metabolism perturbs cytoskeletal dynamics in human astrocytoma cells. J Neurosci Res

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada.
Journal of Neuroscience Research (Impact Factor: 2.59). 05/2009; 87(6):1474-83. DOI: 10.1002/jnr.21965
Source: PubMed


Although aluminum (Al), a known environmental toxin, has been implicated in a variety of neurological disorders, the molecular mechanism responsible for these conditions is not fully understood. In this report, we demonstrate the ability of Al to trigger mitochondrial dysfunction and ineffective adenosine triphosphate (ATP) production. This situation severely affected cytoskeletal dynamics. Whereas the control cells had well-defined structures, the Al-exposed astrocytoma cells appeared as globular structures. Creatine kinase (CK) and profilin-2, two critical modulators of cellular morphology, were markedly diminished in the astrocytoma cells treated with Al. Antioxidants such as alpha-ketoglutarate and N-acetylcysteine mitigated the occurrence of the globular-shaped cells promoted by Al toxicity. Taken together, these data reveal an intricate link between ATP metabolism and astrocytic dysfunction and provide molecular insights into the pathogenesis of Al-induced neurological diseases.

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Available from: Vasu D Appanna, Oct 01, 2015
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    • "These were seeded at a density of 1 Â 10 5 cells/mL in 2 mL of a-MEM + 5% FBS. Cells were grown to 60–70% confluency, treated with H 2 O 2 as described previously and fluorescence microscopy was performed [17]. The cover slips were then exposed to the primary antibody [anti-LDH (1:750), anti-SIRT1 (1:200), anti-acetyl-lysine (1:200)] for 1 h with gentle agitation. "
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    Biochemical and Biophysical Research Communications 10/2014; 454(1):172-177. DOI:10.1016/j.bbrc.2014.10.071 · 2.30 Impact Factor
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    • "In this report, astrocytic cells treated with Al and H 2 O 2 appear to consume lactate rapidly, diverting it directly toward mitochondrial utilization by downregulating cLDH and upregulating mLDH. However, Al-and H 2 O 2 -treated cells have a reduced capacity to perform oxidative metabolism because of a markedly diminished TCA cycle and oxidative phosphorylation (Mailloux et al., 2007a; Lemire et al., 2009, 2011). Instead, these cells were converting lactate to pyruvate to be utilized as an antioxidant. "
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    Journal of Neuroscience Research 04/2014; 92(4). DOI:10.1002/jnr.23338 · 2.59 Impact Factor
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    • "Dysfunctional filamentous actin formation alters the morphology of the cell. Indeed, Al-challenged astrocytes adopt a globular structure rather than exhibiting the extended processes observed Fig. 1 Al toxicity leads to intracellular free Fe that contributes in generating oxidative stress and mitochondrial dysfunction in the control astrocytes (Lemire et al. 2009). These structural changes invoked in response to a disruption in ATP production lead to physiological complications that contribute to the neurological diseases observed under oxidative stress. "
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    ABSTRACT: Metal pollutants are a global health risk due to their ability to contribute to a variety of diseases. Aluminum (Al), a ubiquitous environmental contaminant is implicated in anemia, osteomalacia, hepatic disorder, and neurological disorder. In this review, we outline how this intracellular generator of reactive oxygen species (ROS) triggers a metabolic shift towards lipogenesis in astrocytes and hepatocytes. This Al-evoked phenomenon is coupled to diminished mitochondrial activity, anerobiosis, and the channeling of α-ketoacids towards anti-oxidant defense. The resulting metabolic reconfiguration leads to fat accumulation and a reduction in ATP synthesis, characteristics that are common to numerous medical disorders. Hence, the ability of Al toxicity to create an oxidative environment promotes dysfunctional metabolic processes in astrocytes and hepatocytes. These molecular events triggered by Al-induced ROS production are the potential mediators of brain and liver disorders.
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