Peri-nuclear clustering of mitochondria is triggered during aluminum maltolate induced apoptosis

DeWitt, David A.; Hurd, Jennifer; Fox, Nena; Townsend, Brigitte E.; Griffioen, Kathleen J.; Ghribi, Othman; Savory, John

doi:10.3233/jad-2006-9211

Cited by 24 publications

(17 citation statements)

References 42 publications

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“…Several lines of evidence suggest that apoptosis is the major mode of cell death induced by Al [12], [13]. A study by [14] indicated association of Al induced apoptosis with potential role of p53 signaling in Neuro 2a cells.…”

Section: Introductionmentioning

confidence: 99%

Aluminium Induced Endoplasmic Reticulum Stress Mediated Cell Death in SH-SY5Y Neuroblastoma Cell Line Is Independent of p53

et al. 2014

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Aluminium (Al) is the third most abundant element in the earth’s crust and its compounds are used in the form of house hold utensils, medicines and in antiperspirant etc. Increasing number of evidences suggest the involvement of Al+3 ions in a variety of neurodegenerative disorders including Alzheimer’s disease. Here, we have attempted to investigate the role of Al in endoplasmic reticulum stress and the regulation of p53 during neuronal apoptosis using neuroblastoma cell line. We observed that Al caused oxidative stress by increasing ROS production and intracellular calcium levels together with depletion of intracellular GSH levels. We also studied modulation of key pro- and anti-apoptotic proteins and found significant alterations in the levels of Nrf2, NQO1, pAKT, p21, Bax, Bcl2, Aβ1-40 and Cyt c together with increase in endoplasmic reticulum (ER) stress related proteins like CHOP and caspase 12. However, with respect to the role of p53, we observed downregulation of its transcript as well as protein levels while analysis of its ubiquitination status revealed no significant changes. Not only did Al increase the activities of caspase 9, caspase 12 and caspase 3, but, by the use of peptide inhibitors of specific and pan-caspases, we observed significant protection against neuronal cell death upon inhibition of caspase 12, demonstrating the prominent role of endoplasmic reticulum stress generated responses in Al toxicity. Overall our findings suggest that Al induces ER stress and ROS generation which compromises the antioxidant defenses of neuronal cells thereby promoting neuronal apoptosis in p53 independent pathway.

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Section: Introductionmentioning

confidence: 99%

Aluminium Induced Endoplasmic Reticulum Stress Mediated Cell Death in SH-SY5Y Neuroblastoma Cell Line Is Independent of p53

et al. 2014

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“…The medical importance of understanding vesicle-transporting motors is highlighted by several recent studies, which describe the potential role of axonal transport deficiencies in neurodegenerative conditions such as Alzheimer's disease [10][11][12]. Previously, the overexpression of the microtubule associated protein tau was shown to inhibit kinesin dependent transport [13].…”

Section: Introductionmentioning

confidence: 99%

Force–Velocity Curves of Motor Proteins Cooperating In Vivo

Shtridelman

Cahyuti

Townsend

et al. 2008

Cell Biochem Biophys

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Motor proteins convert chemical energy into work, thereby generating persistent motion of cellular and subcellular objects. The velocities of motor proteins as a function of opposing loads have been previously determined in vitro for single motors. These single molecule "force-velocity curves" have been useful for elucidating motor kinetics and for estimating motor performance under physiological loads due to, for example, the cytoplasmic drag force on transported organelles. Here we report forcevelocity curves for single and multiple motors measured in vivo. Using motion enhanced differential interference contrast (MEDIC) movies of living NT2 (neuron-committed teratocarcinoma) cells at 37°C, three parameters were measured-velocity (v), radius (a), and effective cytoplasmic viscosity (η′)-as they applied to moving vesicles. These parameters were combined in Stokes' equation, F = 6πaη′v, to determine the force, F, required to transport a single intracellular particle at velocity, v. In addition, the number of active motors was inferred from the multimodal pattern seen in a normalized velocity histogram. Using this inference, the resulting in vivo force-velocity curve for a single motor agrees with previously reported in vitro single motor force-velocity curves. Interestingly, however, the curves for two and three motors lie significantly higher in both measured velocity and computed force, which suggests that motors can work cooperatively to attain higher transport forces and velocities.

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“…These events suggest that Al targets mitochondrial mediated apoptosis pathway and mitochondrial changes, following cytotoxic stimuli representing a primary event in apoptotic cell death. Al maltolate induced apoptosis in human NT2 cells via disruption of mitochondrial transport of NT2 cells that exhibited peri-nuclear clustering of mitochondria [43].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Role of Lazaroids Against Aluminium Chloride Poisoning

et al. 2015

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Aluminium (Al) is neurotoxic primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondria being a major site of reactive oxygen species (ROS) production, it seems that the oxidative damage to mitochondrial proteins may underlie the pathogenesis of Al induced neurodegeneration. The present study investigates the effectiveness of the anti-oxidant property of lazaroids (U-74500A), a known lipid peroxidation inhibitor as neuroprotective agent against Al induced neurotoxicity. Al chloride was administered orally at a dose level of 100 mg/kg body wt/day in water and U-74500A was administered at a dose of 0.25 mg/kg body wt i.p. in citrate buffer for a period of 8 weeks on alternate days. Following Al exposure there was a significant increase in lipid peroxidation (LPO), ROS levels and reduction in the activity of mitochondrial complexes in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria. These alterations were also depicted in the histology which shows signs of hypoxia, paucity of neurons in cortical region and loosening of fibers in the white matter. U-74500A co-administration was able to restore alterations in the LPO, ROS levels as well as all the three mitochondrial complexes and caspase expression. Therefore, it is suggested that 21-aminosteroids (lazaroids), by attenuating LPO and mitochondrial dysfunction, holds a promise as an agent that can potentially reduce Al-induced adverse effects in brain.

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Peri-nuclear clustering of mitochondria is triggered during aluminum maltolate induced apoptosis

Cited by 24 publications

References 42 publications

Aluminium Induced Endoplasmic Reticulum Stress Mediated Cell Death in SH-SY5Y Neuroblastoma Cell Line Is Independent of p53

Aluminium Induced Endoplasmic Reticulum Stress Mediated Cell Death in SH-SY5Y Neuroblastoma Cell Line Is Independent of p53

Force–Velocity Curves of Motor Proteins Cooperating In Vivo

Neuroprotective Role of Lazaroids Against Aluminium Chloride Poisoning

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