Mitochondria, oxidative stress and neurodegeneration

Federico, Antonio; Cardaioli, Elena; Pozzo, Paola Da; Formichi, Patrizia; Gallus, Gian Nicola; Radi, Elena

doi:10.1016/j.jns.2012.05.030

Cited by 655 publications

(410 citation statements)

References 97 publications

(96 reference statements)

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“…It is now evident, however, that the concept has been oversimplified, and that the intensity of ROS generation in various brain regions strongly depends on energy metabolism and electrophysiological activity of the brain. 79,80 Furthermore, species-specific traits of animals' behavior are linked to peculiarities of brain oxidative metabolism. These peculiarities are determined by the ratio of oxygen supply and consumption to activities of oxidative enzymes.…”

Section: Oxidative Stress and Mitochondrial Dysfunction In Oxys Ratsmentioning

confidence: 99%

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

et al. 2014

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Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. in recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. in addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. with age, neurodegenerative changes in the brain of OXYS rats become amplified. we have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (AβPP), accumulation of β-amyloid (Aβ), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMDlike retinopathy in OXYS rats is also accompanied by increased accumulation of Aβ in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD.

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Section: Oxidative Stress and Mitochondrial Dysfunction In Oxys Ratsmentioning

confidence: 99%

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

et al. 2014

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“…Accumulation of ROS has been associated with diverse degenerative diseases, such as cancer, neurodegeneration, and obesity-associated metabolic syndrome (2)(3)(4). To minimize detrimental consequences of ROS accumulation, cells are equipped with various antioxidant proteins, including superoxide dismutases, catalases, peroxiredoxins, and sestrins (5)(6)(7).…”

mentioning

confidence: 99%

Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Nam

Jang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Uncoupling protein 1 (Ucp1), which is localized in the mitochondrial inner membrane of mammalian brown adipose tissue (BAT), generates heat by uncoupling oxidative phosphorylation. Upon cold exposure or nutritional abundance, sympathetic neurons stimulate BAT to express Ucp1 to induce energy dissipation and thermogenesis. Accordingly, increased Ucp1 expression reduces obesity in mice and is correlated with leanness in humans. Despite this significance, there is currently a limited understanding of how Ucp1 expression is physiologically regulated at the molecular level. Here, we describe the involvement of Sestrin2 and reactive oxygen species (ROS) in regulation of Ucp1 expression. Transgenic overexpression of Sestrin2 in adipose tissues inhibited both basal and cold-induced Ucp1 expression in interscapular BAT, culminating in decreased thermogenesis and increased fat accumulation. Endogenous Sestrin2 is also important for suppressing Ucp1 expression because BAT from Sestrin2 −/− mice exhibited a highly elevated level of Ucp1 expression. The redox-inactive mutant of Sestrin2 was incapable of regulating Ucp1 expression, suggesting that Sestrin2 inhibits Ucp1 expression primarily through reducing ROS accumulation. Consistently, ROS-suppressing antioxidant chemicals, such as butylated hydroxyanisole and N-acetylcysteine, inhibited cold-or cAMP-induced Ucp1 expression as well. p38 MAPK, a signaling mediator required for cAMP-induced Ucp1 expression, was inhibited by either Sestrin2 overexpression or antioxidant treatments. Taken together, these results suggest that Sestrin2 and antioxidants inhibit Ucp1 expression through suppressing ROSmediated p38 MAPK activation, implying a critical role of ROS in proper BAT metabolism.aging | mouse | homeostasis | β-adrenergic signaling A lthough reactive oxygen species (ROS) are normal products of cellular metabolism, excessive accumulation of ROS resulting from nutritional imbalance and/or environmental stresses can provoke oxidative damage of diverse cellular macromolecules, such as DNA, RNA, and proteins (1). Accumulation of ROS has been associated with diverse degenerative diseases, such as cancer, neurodegeneration, and obesity-associated metabolic syndrome (2-4). To minimize detrimental consequences of ROS accumulation, cells are equipped with various antioxidant proteins, including superoxide dismutases, catalases, peroxiredoxins, and sestrins (5-7). Several ROS-scavenging chemicals or dietary supplements, such as butylated hydroxyanisole (BHA), N-acetylcysteine (NAC), and antioxidant vitamins, can assist with eliminating excessive amounts of ROS (8-10) and were once considered to be potential inhibitors of degenerative diseases associated with aging and obesity (11-13). However, most animal and human clinical studies failed to demonstrate the benefits of dietary antioxidants in restoring metabolic homeostasis or in promoting health and lifespan (13,14).Uncoupling protein 1 (Ucp1) is an anion-carrier protein located in the inner membrane of the mitochondria. By dissipatin...

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“…Overall, this study suggests that Trx1 may play a broader role than previously believed that might include regulating transcription, RNA processing, and nuclear pore function in human cells. Oxidative stress and redox signaling imbalance have been implicated in the development of neurodegenerative diseases and tissue injuries (1). One of the most common features observed in the neuronal tissues of patients with Alzheimer or Parkinson disease is the accumulation of misfolded proteins with oxidative post-translational modifications (2).…”

mentioning

confidence: 99%

“…One of the most common features observed in the neuronal tissues of patients with Alzheimer or Parkinson disease is the accumulation of misfolded proteins with oxidative post-translational modifications (2). Cells have evolved to utilize diverse defense mechanisms to counter the detrimental impact of oxidative post-translational modifications, including the engagement of the thioredoxin (Trx) 1 family of proteins, which includes cytosolic Trx1 and mitochondrial Trx2 in mammalian cells.…”

mentioning

confidence: 99%

Identification of Novel Nuclear Targets of Human Thioredoxin 1

Jain

et al. 2014

Molecular & Cellular Proteomics

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The dysregulation of protein oxidative post-translational modifications has been implicated in stress-related diseases. Trx1 is a key reductase that reduces specific disulfide bonds and other cysteine post-translational modifications. Although commonly in the cytoplasm, Trx1 can also modulate transcription in the nucleus. However, few Trx1 nuclear targets have been identified because of the low Trx1 abundance in the nucleus. Here, we report the large-scale proteomics identification of nuclear Trx1 targets in human neuroblastoma cells using an affinity capture strategy wherein a Trx1C35S mutant is expressed. The wild-type Trx1 contains a conserved C32XXC35 motif, and the C32 thiol initiates the reduction of a target disulfide bond by forming an intermolecular disulfide with one of the oxidized target cysteines, resulting in a transient Trx1-target protein complex. The reduction is rapidly consummated by the donation of a C35 proton to the target molecule, forming a Trx1 C32-C35 disulfide, and results in the concurrent release of the target protein containing reduced thiols. By introducing a point mutation (C35 to S35) in Trx1, we ablated the rapid dissociation of Trx1 from its reduction targets, thereby allowing the identification of 45 putative nuclear Trx1 targets. Unexpectedly, we found that PSIP1, also known as LEDGF, was sensitive to both oxidation and Trx1 reduction at Cys 204. LEDGF is a transcription activator that is vital for regulating cell survival during HIV-1 infection. Overall, this study suggests that Trx1 may play a broader role than previously believed that might include regulating transcription, RNA processing, and nuclear pore function in human cells. Molecular

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Mitochondria, oxidative stress and neurodegeneration

Cited by 655 publications

References 97 publications

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species

Identification of Novel Nuclear Targets of Human Thioredoxin 1

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