The Antioxidant N-Acetylcysteine Prevents the Mitochondrial Fragmentation Induced by Soluble Amyloid-F Peptide Oligomers

SanMartín, Carol D.; Adasme, Tatiana; Hidalgo, Cecilia; Paula-Lima, Andrea

doi:10.1159/000334901

Cited by 36 publications

(50 citation statements)

References 29 publications

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“…Recent evidence has revealed that Aβ oligomers, which are recognized as one of the most toxic forms of the Aβ peptide, interfere with mitochondrial dynamics (Hefti et al, 2013;Sanmartin et al, 2012). Overexpression of Aβ in M17 cells affects the expression of different proteins involved in mitochondrial fission and fusion, such as DLP1, Fis1, and OPA1 (Wang et al, 2008).…”

Section: Mitochondrial Dysfunction and Iron Accumulation In Admentioning

confidence: 99%

Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

et al. 2015

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Section: Mitochondrial Dysfunction and Iron Accumulation In Admentioning

confidence: 99%

Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

et al. 2015

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“…We reported previously that amyloid β peptide oligomers (AβOs) induce anomalous Ca 2+ signals in primary hippocampal neurons; these signals arise initially from Ca 2+ entry through N -Methyl- D -aspartate (NMDA) receptors and are subsequently amplified via RyR channels co-stimulated by Ca 2+ entry signals and the increased ROS levels produced by AβOs (Paula-Lima et al, 2011; SanMartín et al, 2012a). Furthermore, the levels of RyR2, which is the most abundant RyR isoform expressed in the brain (Giannini et al, 1995), are 20% lower in the brain from AD cases compared to controls (Kelliher et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, the mitochondrial Ca 2+ uniporter complex mediates mitochondrial Ca 2+ uptake following RyR activation in cardiac muscle fibrils (Szalai et al, 2000) and IP 3 R-mediated Ca 2+ release in liver (Csordas et al, 2006). Intracellular Ca 2+ channels also generate Ca 2+ signals that affect the mitochondrial network in neurons, since the selective RyR agonist 4-chloro-m-cresol (4-CMC) induces mitochondrial fragmentation in neurons (SanMartín et al, 2012a), indicating that Ca 2+ release from the ER has a pivotal role in shaping mitochondrial dynamics in hippocampal neurons.…”

Section: Introductionmentioning

confidence: 99%

“…We also reported that this fragmentation process requires functional RyR channels and that RyR-mediated mitochondrial Ca 2+ uptake does not occur in fragmented mitochondria, probably due to impaired coupling of the mitochondrial Ca 2+ uniporter with RyR channels (SanMartín et al, 2014). In addition, we found that pre-incubation of neurons with the antioxidant agent N -acetyl cysteine (NAC), a physiological precursor of cellular glutathione (GSH) synthesis, prevents the mitochondrial network fragmentation and RyR2 knockdown mediated by RyR channel activation in response to AβOs (SanMartín et al, 2012a; Lobos et al, 2016). These combined results corroborate the key role played by ROS and RyR on mitochondrial dynamics.…”

Section: Introductionmentioning

confidence: 99%

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RyR2-Mediated Ca2+ Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers

SanMartín

Veloso

Adasme

et al. 2017

Front. Mol. Neurosci.

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Amyloid β peptide oligomers (AβOs), toxic aggregates with pivotal roles in Alzheimer’s disease, trigger persistent and low magnitude Ca2+ signals in neurons. We reported previously that these Ca2+ signals, which arise from Ca2+ entry and subsequent amplification by Ca2+ release through ryanodine receptor (RyR) channels, promote mitochondrial network fragmentation and reduce RyR2 expression. Here, we examined if AβOs, by inducing redox sensitive RyR-mediated Ca2+ release, stimulate mitochondrial Ca2+-uptake, ROS generation and mitochondrial fragmentation, and also investigated the effects of the antioxidant N-acetyl cysteine (NAC) and the mitochondrial antioxidant EUK-134 on AβOs-induced mitochondrial dysfunction. In addition, we studied the contribution of the RyR2 isoform to AβOs-induced Ca2+ release, mitochondrial Ca2+ uptake and fragmentation. We show here that inhibition of NADPH oxidase type-2 prevented the emergence of RyR-mediated cytoplasmic Ca2+ signals induced by AβOs in primary hippocampal neurons. Treatment with AβOs promoted mitochondrial Ca2+ uptake and increased mitochondrial superoxide and hydrogen peroxide levels; ryanodine, at concentrations that suppress RyR activity, prevented these responses. The antioxidants NAC and EUK-134 impeded the mitochondrial ROS increase induced by AβOs. Additionally, EUK-134 prevented the mitochondrial fragmentation induced by AβOs, as previously reported for NAC and ryanodine. These findings show that both antioxidants, NAC and EUK-134, prevented the Ca2+-mediated noxious effects of AβOs on mitochondrial function. Our results also indicate that Ca2+ release mediated by the RyR2 isoform causes the deleterious effects of AβOs on mitochondrial function. Knockdown of RyR2 with antisense oligonucleotides reduced by about 50% RyR2 mRNA and protein levels in primary hippocampal neurons, decreased by 40% Ca2+ release induced by the RyR agonist 4-chloro-m-cresol, and significantly reduced the cytoplasmic and mitochondrial Ca2+ signals and the mitochondrial fragmentation induced by AβOs. Based on our results, we propose that AβOs-induced Ca2+ entry and ROS generation jointly stimulate RyR2 activity, causing mitochondrial Ca2+ overload and fragmentation in a feed forward injurious cycle. The present novel findings highlight the specific participation of RyR2-mediated Ca2+ release on AβOs-induced mitochondrial malfunction.

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“…At the cellular level, AbOs induce oxidative stress (De Felice et al 2007), promote excitotoxicity (Alberdi et al 2010) and cause a swift and prolonged increase in intracellular Ca 2? concentration (Paula-Lima et al 2011;SanMartin et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Sub-lethal levels of amyloid β-peptide oligomers decrease non-transferrin-bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons

et al. 2012

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Two major lesions are pathological hallmarks in Alzheimer's disease (AD): the presence of neurofibrillary tangles formed by intracellular aggregates of the hyperphosphorylated form of the cytoskeletal tau protein, and of senile plaques composed of extracellular aggregates of amyloid beta (Aβ) peptide. Current hypotheses regard soluble amyloid beta oligomers (AβOs) as pathological causative agents in AD. These aggregates cause significant calcium deregulation and mediate neurotoxicity by disrupting synaptic activity. Additionally, the presence of high concentrations of metal ions such as copper, zinc, aluminum and iron in neurofibrillary tangles and senile plaques, plus the fact that they accelerate the rate of formation of Aβ fibrils and AβOs in vitro, suggests that accumulation of these metals in the brain is relevant to AD pathology. A common cellular response to AβOs and transition metals such as copper and iron is the generation of oxidative stress, with the ensuing damage to cellular components. Using hippocampal neurons in primary culture, we report here the effects of treatment with AβOs on the (+)IRE and (-)IRE mRNA levels of the divalent metal transporter DMT1. We found that non-lethal AβOs concentrations decreased DMT1 (-)IRE without affecting DMT1 (+)IRE mRNA levels, and inhibited non-transferrin bound iron uptake. In addition, since both iron and AβOs induce oxidative damage, we studied whether their neurotoxic effects are synergistic. In the range of concentrations and times used in this study, AβOs did not potentiate iron-induced cell death while iron chelation did not decrease AβOs-induced cell death. The lack of synergism between iron and AβOs suggests that these two neurotoxic agents converge in a common target, which initiates signaling processes that promote neurodegeneration.

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The Antioxidant N-Acetylcysteine Prevents the Mitochondrial Fragmentation Induced by Soluble Amyloid-F Peptide Oligomers

Cited by 36 publications

References 29 publications

Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders

RyR2-Mediated Ca2+ Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers

Sub-lethal levels of amyloid β-peptide oligomers decrease non-transferrin-bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons

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