共查询到20条相似文献,搜索用时 15 毫秒
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In mitochondria, oxidative phosphorylation and enzymatic oxidation of biogenic amines by monoamine oxidase produce reactive
oxygen and nitrogen species, which are proposed to cause neuronal cell death in neurodegenerative disorders, including Parkinson’s
and Alzheimer’s disease. In these disorders, mitochondrial dysfunction, increased oxidative stress, and accumulation of oxidation-modified
proteins are involved in cell death in definite neurons. The interactions among these factors were studied by use of a peroxynitrite-generating
agent, N-morpholino sydnonimine (SIN-1) and an inhibitor of complex I, rotenone, in human dopaminergic SH-SY5Y cells. In control cells,
peroxynitrite nitrated proteins, especially the subunits of mitochondrial complex I, as 3-nitrotyrosine, suggesting that neurons
are exposed to constant oxidative stress even under physiological conditions. SIN-1 and an inhibitor of proteasome, carbobenzoxy-l-isoleucyl-γ-t-butyl-l-analyl-l-leucinal (PSI), increased markedly the levels of nitrated proteins with concomitant induction of apoptosis in the cells.
Rotenone induced mitochondrial dysfunction and accumulation and aggregation of proteins modified with acrolein, an aldehyde
product of lipid peroxidation in the cells. At the same time, the activity of the 20S β-subunit of proteasome was reduced
significantly, which degrades oxidative-modified protein. The mechanism was proved to be the result of the modification of
the 20S β-subunit with acrolein and to the binding of other acrolein-modified proteins to the 20S β-subunit.
Increased oxidative stress caused by SIN-1 treatment induced a decline in the mitochondrial membrane potential, ΔΨm, and activated
mitochondrial apoptotic signaling and induced cell death in SH-SY5Y cells. As another pathway, p38 mitogen-activated protein
(MAP) kinase and exracellular signal-regulated kinase (ERK) mediated apoptosis induced by SIN-1. On the other hand, a series
of neuroprotective propargylamine derivatives, including rasagiline [N-propargyl-1(R)aminoindan]and (−)deprenyl, intervened in the activation of apoptotic cascade by reactive oxygen species-reactive nitrogen
species in mitochondria through stabilization of the membrane potential, ΔΨm. In addition, rasagiline induced antiapoptotic
Bcl-2 and glial cell line-derived neurotrophic factor (GDNF) in SH-SY5Y cells, which was mediated by the ERK-nuclear factor
(NF)-κB pathway. These results are discussed in relation to the interaction of oxidative stress and mitochondria in the regulation
of neuronal death and survival in neurodegenerative diseases. 相似文献
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Oxidative stress hypothesis of aging 总被引:9,自引:0,他引:9
Sohal RS 《Free radical biology & medicine》2002,33(5):573-574
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Shao C Roberts KN Markesbery WR Scheff SW Lovell MA 《Free radical biology & medicine》2006,41(1):77-85
Oxidative damage is proposed as a key mediator of exacerbated morphological responses and deficits in behavioral recovery in aged subjects with traumatic brain injury (TBI). In the present study, we show exacerbated loss of tissue in middle aged (12 months) and aged (22 months) Fisher-344 rats compared to young animals (3 months) subjected to moderate TBI. Analysis of 4-hydroxynonenal (4-HNE) and acrolein, neurotoxic by-products of lipid peroxidation, shows significant (P < 0.05) age-dependent increases in ipsilateral (IP) hippocampus 1 and 7 days post injury. In IP cortex, 4-HNE was significantly elevated 1 day post injury in all age groups, and both 4-HNE and acrolein were elevated in middle aged and aged animals 7 days post injury. Comparison of antioxidant enzyme activities shows significant (P < 0.05) age-dependent decreases of manganese superoxide dismutase in IP hippocampus and cortex 1 and 7 days post injury. Glutathione reductase activity also showed an age-dependent decrease. Overall, our data show increased levels of oxidative damage, diminished antioxidant capacities, and increased tissue loss in TBI in aging. 相似文献
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Oxidative stress and aging in Caenorhabditis elegans 总被引:2,自引:0,他引:2
Ishii N 《Free radical research》2000,33(6):857-864
Much attention has been focused on the hypothesis that oxidative damage plays in cellular and organismal aging. A mev-1 (kn1) mutant of Caenorhabditis elegans, isolated on the basis of its methyl viologen (paraquat) hypersensitivity, is also hypersensitive to elevated oxygen levels. Unlike the wild type, its life span decreases dramatically as oxygen concentrations are increased from 1% to 60%. Strains, which bear this mutation, accumulate fluorescent materials and protein carbonyl groups, markers of aging, at faster rates than the wild type. We have cloned mev-1 gene by transformation rescue and found that it is, in fact, the previously sequenced gene (cyt-1) that encodes succinate dehydrogenase cytochrome b. A missense mutation abolishes complex II activity in the mitochondrial membrane but not succinate dehydrogenase enzyme activity per se. These data suggest that CYT-1 directly participates in electron transport from FADH2 to coenzyme Q. Moreover, mutational inactivation of this process renders animals susceptible to oxidative stress and, as a result, leads to premature aging. 相似文献
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Oxidative insults, whether over-excitation, excessive release of glutamate or ATP caused by stroke, ischemia or inflammation, exposure to ionizing radiation, heavy-metal ions or oxidized lipoproteins may initiate various signaling cascades leading to apoptotic cell death and neurodegenerative disorders. Among the various reactive oxygen species (ROS) generated in the living organism, hydroxyl and peroxynitrite are the most potent and can damage proteins, lipids and nucleic acids. It appears that some natural antioxidants (tocopherol, ascorbic acid and glutathione) and defense enzyme systems (superoxide dismutase, catalase and glutathione peroxidase) may provide some protection against oxidative damage. Recent findings indicate several polyphenols and antioxidant drugs (probucol, seligilline) are effective in protecting the cells from ROS attack. Further development of these antioxidant molecules may be of value in preventing the development of neurodegenerative diseases. 相似文献
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Ivanina AV Sokolova IM Sukhotin AA 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2008,150(1):53-61
The mechanisms of aging are not well understood in animals with continuous growth such as fish, reptiles, amphibians and numerous invertebrates, including mollusks. We studied the effects of age on oxidative stress, cellular defense mechanisms (including two major antioxidant enzymes, superoxide dismutase (SOD) and catalase), and molecular chaperones in two mollusks--eastern oysters Crassostrea virginica and hard clams Mercenaria mercenaria. In order to detect the age-related changes in these parameters, correction for the effects of size was performed where appropriate to account for growth-related dilution. Fluorescent age pigments accumulated with age in both species. Protein carbonyls did not change with age or size indicating that they are not a good marker of aging in mollusks possibly due to the fast turnover and degradation of oxidized proteins in growing tissues. SOD did not show a compensatory increase with aging in either species, while catalase significantly decreased with age. Mitochondrial heat shock protein (HSP60) decreased with age in mollusks suggesting an age-related decline in mitochondrial chaperone protection. In contrast, changes in cytosolic chaperones were species-specific. HSP70 increased and HSP90 declined with age in clams, whereas in oysters HSP70 expression did not change, and HSP90 increased with aging. 相似文献
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The aetiology of most neurodegenerative disorders is multifactorial and consists of an interaction between environmental factors and genetic predisposition. Free radicals derived primarily from molecular oxygen have been implicated and considered as associated risk factors for a variety of human disorders including neurodegenerative diseases and aging. Damage to tissue biomolecules, including lipids, proteins and DNA, by free radicals is postulated to contribute importantly to the pathophysiology of oxidative stress. The potential of environmental exposure to metals, air pollution and pesticides as well as diet as risk factors via the induction of oxidative stress for neurodegenerative diseases and aging is discussed. The role of genetic background is discussed on the light of the oxidative stress implication, focusing on both complex neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) and monogenic neurological disorders (Huntington's disease, Ataxia telangiectasia, Friedreich Ataxia and others). Emphasis is given to role of the repair mechanisms of oxidative DNA damage in delaying aging and protecting against neurodegeneration. The emerging interplay between environmental-induced oxidative stress and epigenetic modifications of critical genes for neurodegeneration is also discussed. 相似文献
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Giuseppe Paradies Giuseppe Petrosillo Valeria Paradies Francesca M. Ruggiero 《Free radical biology & medicine》2010,48(10):1286-1295
Aging is a natural, complex, and multifactorial biological process associated with impairment of bioenergetic function, increased oxidative stress, attenuated ability to respond to stresses, and increased risk of contracting age-associated diseases. Oxidative stress is widely thought to underpin many aging processes. The mitochondrion, the powerhouse of the cell, is considered the most important cellular organelle to contribute to the aging process, mainly through respiratory chain dysfunction and formation of reactive oxygen species, leading to damage to mitochondrial proteins, lipids, and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, is known to be intimately involved in several mitochondrial bioenergetic processes as well as mitochondrial-dependent steps in apoptosis and mitochondrial membrane stability and dynamics. Alterations to cardiolipin structure, content, and acyl chain composition have been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions and aging. In this review, we discuss several aspects of mitochondrial bioenergetic alterations in aging and the role played by reactive oxygen species and cardiolipin in these alterations. 相似文献
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Brain aging is associated with a progressive imbalance between antioxidant defenses and intracellular concentrations of reactive oxygen species (ROS) as exemplified by increases in products of lipid peroxidation, protein oxidation, and DNA oxidation. Oxidative conditions cause not only structural damage but also changes in the set points of redox-sensitive signaling processes including the insulin receptor signaling pathway. In the absence of insulin, the otherwise low insulin receptor signaling is strongly enhanced by oxidative conditions. Autophagic proteolysis and sirtuin activity, in turn, are downregulated by the insulin signaling pathway, and impaired autophagic activity has been associated with neurodegeneration. In genetic studies, impairment of insulin receptor signaling causes spectacular lifespan extension in nematodes, fruit flies, and mice. The predicted effects of age-related oxidative stress on sirtuins and autophagic activity and the corresponding effects of antioxidants remain to be tested experimentally. However, several correlates of aging have been shown to be ameliorated by antioxidants. Oxidative damage to mitochondrial DNA and the electron transport chain, perturbations in brain iron and calcium homeostasis, and changes in plasma cysteine homeostasis may altogether represent causes and consequences of increased oxidative stress. Aging and cognitive decline thus appear to involve changes at multiple nodes within a complex regulatory network. 相似文献
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Elis Eleutherio Aline de Araujo Brasil Mauro Braga França Diego Seixas Gomes de Almeida Germana Breves Rona Rayne Stfhany Silva Magalhães 《Fungal biology》2018,122(6):514-525
The yeast Saccharomyces cerevisiae has played a vital role in the understanding of the molecular basis of aging and the relationship of aging process with oxidative stress (non-homeostatic accumulation of Reactive Oxygen Species, ROS). The mammalian and yeast antioxidant responses are similar and over 25 % of human-degenerative disease related genes have close homologues in yeast. The reduced genetic redundancy of yeast facilitates visualization of the effect of a deleted or mutated gene. By manipulating growth conditions, yeast cells can survive only fermenting (low ROS levels) or respiring (increased ROS levels), which facilitates the elucidation of the mechanisms involved with acquisition of tolerance to oxidative stress. Furthermore, the yeast databases are the most complete of all eukaryotic models. In this work, we highlight the value of S. cerevisiae as a model to investigate the oxidative stress response and its potential impact on aging and age-related diseases. 相似文献
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A wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) with aging has been observed in animals and humans. These include (i) decline in mitochondrial respiratory function; (ii) increase in mitochondrial production of reactive oxygen species (ROS) and the extent of oxidative damage to DNA, proteins, and lipids; (iii) accumulation of point mutations and large-scale deletions of mtDNA; and (iv) enhanced apoptosis. Recent studies have provided abundant evidence to substantiate the importance of mitochondrial production of ROS in aging. On the other hand, somatic mtDNA mutations can cause premature aging without increasing ROS production. In this review, we focus on the roles that ROS play in the aging-associated decline of mitochondrial respiratory function, accumulation of mtDNA mutations, apoptosis, and alteration of gene expression profiles. Taking these findings together, we suggest that mitochondrial dysfunction, enhanced oxidative stress, subsequent accumulation of mtDNA mutations, altered expression of a few clusters of genes, and apoptosis are important contributors to human aging. 相似文献
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Erythrocyte aging in neurodegenerative disorders. 总被引:1,自引:0,他引:1
L De Franceschi O Olivieri R Corrocher 《Cellular and molecular biology, including cyto-enzymology》2004,50(2):179-185
In the present paper, we have reviewed the principal studies on red cell membrane abnormalities associated with neurodegenerative disorders. In the literature, two lines of investigation may be recognized: one based on the hypothesis of the presence of an oxidative environment responsible for red cell oxidative damage in Alzheimer's disease (AD), Alzheimer's dementia type (DAT) and Parkinson' disease (PD); the other one based on the identification of structural and/or functional abnormalities in red cell membrane band 3 and/or in red cell membrane lipid composition in "neuroacanthocytosis". In AD, DAT and PD patients, an increased red cell membrane lipid peroxidation suggests an increase red cell oxidative damages and precocious red cell aging. In "neuroacanthocytosis", grouping chorea-acanthocytosis, Mcleod syndrome and abetalipoproteinemia, the red cells are characterized by thorn or spur-like protrusions, known as "acanthocytes". The presence of circulating acanthocytes, characterized by abnormalities in red cell band 3 structure and/or function, is associated with increase levels of anti-band 3 antibodies which are physiologically produced against aged red cells and are known to mediate red cell removal from the peripheral circulation by macrophages. We have reviewed the mechanism(s) of the loss of red cell membrane stability and of the precocious red cell aging in neurodegenerative disorders. 相似文献
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Comparison of 5 d old stationary cultures of Saccharomyces cerevisiae and of cultures aged for 3 months revealed increased generation of reactive oxygen species assessed by 2', 7'-dichlorofluorescin oxidation, decreased activity of superoxide dismutase, decreased content of glutathione and increased protein carbonyl content during prolonged incubation of stationary yeast cultures. These results point to the occurrence of oxidative stress during aging of stationary cultures of the yeast. The magnitude of this stress was augmented in antioxidant-deficient strains, devoid of superoxide dismutases and catalases, and of decreased glutathione content. 相似文献
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Rat liver mitochondria undergo extensive swelling when they are incubated in hypotonic sucrose medium containing 5 mm Pi. After 30 min of swelling at 25 °C, a three- to fourfold increase in volume has occurred, accompanied by gross disorganization of the matrix as observed by electron microscopy. Succinate-supported respiration was unchanged, but the respiration of NAD-linked substrates was reduced and there was a complete and irreversible loss of phosphorylation in both cases. β-Hydroxybutyrate-supported respiration was regained completely on addition of NAD to the swollen mitochondria. α-Ketoglutarate- and malate + pyruvate-supported respiration was only partially restored by the addition of NAD. This inhibition of respiration in swollen mitochondria may be due to a disorganization of a putative complex of Krebs cycle enzymes on the inner surface of the inner membrane. 相似文献
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The mitochondrial genome encodes just a small number of subunits of the respiratory chain. All the other mitochondrial proteins are encoded in the nucleus and produced in the cytosol. Various enzymes participate in the activation and intramitochondrial transport of imported proteins. To finally take their place in the various mitochondrial compartments, the targeting signals of imported proteins have to be cleaved by mitochondrial processing peptidases. Mitochondria must also be able to eliminate peptides that are internally synthesized in excess, as well as those that are improperly assembled, and those with abnormal conformation caused by mutation or oxidative damage. Damaged mitochondrial proteins can be removed in two ways: either through lysosomal autophagy, that can account for at most 25-30% of the biochemically estimated rates of average mitochondrial catabolism; or through an intramitochondrial proteinolytic pathway. Mitochondrial proteases have been extensively studied in yeast, but evidence in recent years has demonstrated the existence of similar systems in mammalian cells, and has pointed to the possible importance of mitochondrial proteolytic enzymes in human diseases and ageing. A number of mitochondrial diseases have been identified whose mechanisms involve proteolytic dysfunction. Similar mechanisms probably play a role in diminished resistance to oxidative stress, and in the aging process. In this paper we review current knowledge of mammalian mitochondrial proteolysis, under normal conditions and in several disease states, and we propose an etiological classification of human diseases characterized by a decline or loss of function of mitochondrial proteolytic enzymes. 相似文献