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1.
Schapira AH 《Neurochemical research》2008,33(12):2502-2509
Mitochondria play a pivotal role in mammalian cell metabolism, hosting a number of important biochemical pathways including
oxidative phosphorylation. As might be expected from this fundamental contribution to cell function, abnormalities of mitochondrial
metabolism are a common cause of human disease. Primary mutations of mitochondrial DNA result in a diverse group of disorders
often collectively referred to as the mitochondrial encephalomyopathies. Perhaps more importantly in numerical terms are those
neurodegenerative diseases caused by mutations of nuclear genes encoding mitochondrial proteins. Finally there are mitochondrial
abnormalities induced by secondary events e.g. oxidative stress that may contribute to senescence, and environmental toxins
that may cause disease either alone or in combination with a genetic predisposition.
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella. 相似文献
2.
Mitochondrial Dysfunction and Reactive Oxygen Species in Excitotoxicity and Apoptosis: Implications for the Pathogenesis of Neurodegenerative Diseases 总被引:24,自引:0,他引:24
In recent years we have witnessed a major interest in the study of the role of mitochondria, not only as ATP producers through oxidative phosphorylation but also as regulators of intracellular Ca2+ homeostasis and endogenous producers of reactive oxygen species (ROS). Interestingly, the mitochondria have been also implicated as central executioners of cell death. Increased mitochondrial Ca2+ overload as a result of excitotoxicity has been associated with the generation of superoxide and may induce the release of proapoptotic mitochondrial proteins, proceeding through DNA fragmentation/condensation and culminating in cell demise by apoptosis and/or necrosis. In addition, these processes have been implicated in the pathogenesis of many neurodegenerative diseases, which share several features of cell death: selective brain areas undergo neurodegeneration, involving mitochondrial dysfunction (mitochondrial complexes are affected), loss of intracellular Ca2+ homeostasis, excitotoxicity, and the extracellular or intracellular accumulation of insoluble protein aggregates in the brain. 相似文献
3.
Venkateswaran Natarajan Ritu Chawla Tania Mah Rajesh Vivekanandan Shu Yi Tan Priscila Y Sato Karthik Mallilankaraman 《Proteomics》2020,20(5-6)
Aging is a natural biological process in living organisms characterized by receding bioenergetics. Mitochondria are crucial for cellular bioenergetics and thus an important contributor to age‐related energetics deterioration. In addition, mitochondria play a major role in calcium signaling, redox homeostasis, and thermogenesis making this organelle a major cellular component that dictates the fate of a cell. To maintain its quantity and quality, mitochondria undergo multiple processes such as fission, fusion, and mitophagy to eliminate or replace damaged mitochondria. While this bioenergetics machinery is properly protected, the functional decline associated with age and age‐related metabolic diseases is mostly a result of failure in such protective mechanisms. In addition, metabolic by‐products like reactive oxygen species also aid in this destructive pathway. Mitochondrial dysfunction has always been thought to be associated with diseases. Moreover, studies in recent years have pointed out that aging contributes to the decay of mitochondrial health by promoting imbalances in key mitochondrial‐regulated pathways. Hence, it is crucial to understand the nexus of mitochondrial dysfunction in age‐related diseases. This review focuses on various aspects of basic mitochondrial biology and its status in aging and age‐related metabolic diseases. 相似文献
4.
Calabrese V Cornelius C Mancuso C Pennisi G Calafato S Bellia F Bates TE Giuffrida Stella AM Schapira T Dinkova Kostova AT Rizzarelli E 《Neurochemical research》2008,33(12):2444-2471
The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including
protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in
the aging brain. Alzheimer’s and Parkinson’s diseases or Friedreich ataxia are neurological diseases sharing, as a common
denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis
of these so called “protein conformational diseases”. The central nervous system has evolved the conserved mechanism of unfolded
protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved
in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective
heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show
that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health
and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or
intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may
be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism
and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses
on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins,
as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently,
the neuroprotective roles of dietary antioxidants including curcumin, acetyl-l-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although
the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate
neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress
response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella. 相似文献
5.
G. B. Stefano N. Pilonis R. Ptacek J. Raboch M. Vnukova R. M. Kream 《Cellular and molecular neurobiology》2018,38(6):1197-1206
It has become apparent that the molecular and biochemical integrity of interactive families, genera, and species of human gut microflora is critically linked to maintaining complex metabolic and behavioral processes mediated by peripheral organ systems and central nervous system neuronal groupings. Relatively recent studies have established intrinsic ratios of enterotypes contained within the human microbiome across demographic subpopulations and have empirically linked significant alterations in the expression of bacterial enterotypes with the initiation and persistence of several major metabolic and psychiatric disorders. Accordingly, the goal of our review is to highlight potential thematic/functional linkages of pathophysiological alterations in gut microbiota and bidirectional gut–brain signaling pathways with special emphasis on the potential roles of gut dysbiosis on the pathophysiology of psychiatric illnesses. We provide critical discussion of putative thematic linkages of Parkinson’s disease (PD) data sets to similar pathophysiological events as potential causative factors in the development and persistence of diverse psychiatric illnesses. Finally, we include a concise review of preclinical paradigms that involve immunologically–induced GI deficits and dysbiosis of maternal microflora that are functionally linked to impaired neurodevelopmental processes leading to affective behavioral syndromes in the offspring. 相似文献
6.
Aguiar AS Tuon T Pinho CA Silva LA Andreazza AC Kapczinski F Quevedo J Streck EL Pinho RA 《Neurochemical research》2008,33(1):51-58
There are conflicts between the effects of free radical over-production induced by exercise on neurotrophins and brain oxidative
metabolism. The objective of this study was to investigate the effects of intense physical training on brain-derived neurotrophic
factor (BDNF) levels, COX activity, and lipoperoxidation levels in mice brain cortex. Twenty-seven adult male CF1 mice were
assigned to three groups: control untrained, intermittent treadmill exercise (3 × 15 min/day) and continuous treadmill exercise
(45 min/day). Training significantly (P < 0.05) increased citrate synthase activity when compared to untrained control. Blood lactate levels classified the exercise
as high intensity. The intermittent training significantly (P < 0.05) reduced in 6.5% the brain cortex COX activity when compared to the control group. BDNF levels significantly (P < 0.05) decreased in both exercise groups. Besides, continuous and intermittent exercise groups significantly (P < 0.05) increased thiobarbituric acid reactive species levels in the brain cortex. In summary, intense exercise promoted
brain mitochondrial dysfunction due to decreased BDNF levels in the frontal cortex of mice. 相似文献
7.
Repeated low-dose exposure to carbofuran exerts its neurotoxic effects by non-cholinergic mechanisms. Emerging evidence indicates
that oxidative stress plays an important role in carbofuran neurotoxicity after sub-chronic exposure. The purpose of the present
study is to evaluate the role of mitochondrial oxidative stress and dysfunction as a primary event responsible for neurotoxic
effects observed after sub-chronic carbofuran exposure. Carbofuran was administered to rats at a dose of 1 mg/kg orally for
a period of 28 days. There was a significant inhibition in the activity of acetylcholinesterase (66.6%) in brain samples after
28 days of carbofuran exposure. Mitochondrial respiratory chain functions were assessed in terms of MTT (3-(4, 5-dimethylthiazolyl-2)-2,
5-diphenyltetrazolium bromide) reduction and activity of succinate dehydrogenase in isolated mitochondria. It was observed
that carbofuran exposure significantly inhibited MTT reduction (31%) and succinate dehydrogenase activity (57%). This was
accompanied by decrease in low-molecular weight thiols (66.6%) and total thiols (37.4%) and an increase in lipid peroxidation
(43.7%) in the mitochondria isolated from carbofuran-exposed rat brain. The changes in mitochondrial oxidative stress and
functions were associated with impaired cognitive and motor functions in the animals exposed to carbofuran as compared to
the control animals. Based on these results, it is clear that carbofuran exerts its neurotoxicity by impairing mitochondrial
functions leading to oxidative stress and neurobehavioral deficits. 相似文献
8.
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10.
Oxidative Damage and Cognitive Dysfunction: Antioxidant Treatments to Promote Healthy Brain Aging 总被引:1,自引:0,他引:1
Head E 《Neurochemical research》2009,34(4):670-678
Oxidative damage in the brain may lead to cognitive impairments in aged humans. Further, in age-associated neurodegenerative
disease, oxidative damage may be exacerbated and associated with additional neuropathology. Epidemiological studies in humans
show both positive and negative effects of the use of antioxidant supplements on healthy cognitive aging and on the risk of
developing Alzheimer disease (AD). This contrasts with consistent behavioral improvements in aged rodent models. In a higher
mammalian model system that naturally accumulates human-type pathology and cognitive decline (aged dogs), an antioxidant enriched
diet leads to rapid learning improvements, memory improvements after prolonged treatment and cognitive maintenance. Cognitive
benefits can be further enhanced by the addition of behavioral enrichment. In the brains of aged treated dogs, oxidative damage
is reduced and there is some evidence of reduced AD-like neuropathology. In combination, antioxidants may be beneficial for
promoting healthy brain aging and reducing the risk of neurodegenerative disease.
Special issue article in honor of Dr. Akitne Mori. 相似文献
11.
拥有健康的晚年是每一个人的祈盼,这也是目前应对即将到来的社会老龄化危机而需要解决的重要课题.实现健康衰老需要对人类衰老发生的机制有深入的了解,比如在此过程中扮演着重要角色的线粒体的研究.线粒体是细胞能量和自由基代谢中心,也是细胞凋亡调控中心,并在信号转导和基因表达调控中发挥重要作用.线粒体一旦受损,一方面能量代谢发生紊乱,另一方面产生大量自由基,影响细胞的正常生长,并导致细胞甚至机体的衰老.正常情况下,细胞通过自噬溶酶体机制选择性清除受损伤和不需要的线粒体,这是线粒体质量控制的重要机制.研究发现,线粒体质量控制异常可能在衰老发生过程中起关键作用.限食及增强运动能有效促进线粒体质量控制,改善线粒体功能并延缓衰老. 相似文献
12.
R. Vogel G. Jennemann J. Seitz H. Wiesinger B. Hamprecht 《Journal of neurochemistry》1998,71(2):844-852
Abstract: To elucidate the cellular location of mitochondrial malic enzyme in brain, immunocytochemical studies were performed. For this purpose, mitochondrial malic enzyme was purified to apparent homogeneity from bovine brain and used for the immunization of rabbits. Subjecting the antiserum to affinity purification on immobilized antigen as an absorbent yielded a purified immunoreactive antibody preparation, which was characterized by probing cytosolic and mitochondrial fractions of bovine and rat brain in western blotting. As neither crossreactivity with cytosolic malic enzyme nor immunoreactivity against other proteins could be observed, the antibody preparation was found suitable for immunocytochemistry. By using sections of perfusion-fixed rat brain, considerable resolution was achieved at the light-microscopic level. Distinct and specific staining of neurons was observed; in contrast, no staining of astrocytes and possibly unspecific staining within the nuclei of oligodendrocytes were obtained. From these data, it is concluded that mitochondrial malic enzyme is located in neurons; however, in astrocytes, the enzyme appears to be either lacking or present at a much lower level. A protective role against oxidative stress in neurons is proposed for mitochondrial malic enzyme. 相似文献
13.
Mattson MP 《Neurochemical research》2003,28(11):1631-1637
This article recounts some of the scientific endeavors of Carl W. Cotman (CWC) during his journeys through the cellular circuitry of the mammalian brain. I have selected for consideration his findings that have been an important impetus for my own research; in several cases our different experiments have provided complementary data to support an hypothesis. Three examples are (i) Carl's studies of the roles of glutamate in synaptic transmission and plasticity in the adult brain and my studies of how glutamate regulates neurite outgrowth and cell survival in brain development; (ii) his and our studies of the mechanisms whereby amyloid -peptide damages and kills neurons; and (iii) Carl's evidence that physical activity regulates neurotrophin levels in the brain and our evidence that dietary restriction has similar effects and is neuroprotective. In case you have not yet realized how I chose a title for this article it is because Carl has a (very distant) connection with Charles Darwin—Darwin sailed on a vessel called the Beagle and Carl has studied beagle dogs, establishing them as a model for understanding the neurobiology of human brain aging. 相似文献
14.
Anne Chomyn 《Journal of bioenergetics and biomembranes》2001,33(3):251-257
Sixteen years ago, we demonstrated, by immunological and biochemical approaches, that seven subunits of complex I are encoded in mitochondrial DNA (mtDNA) and synthesized on mitochondrial ribosomes in mammalian cells. More recently, we carried out a biochemical, molecular, and cellular analysis of a mutation in the gene for one of these subunits, ND4, that causes Leber's hereditary optic neuropathy (LHON). We demonstrated that, in cells carrying this mutation, the mtDNA-encoded subunits of complex I are assembled into a complex, but the rate of complex I-dependent respiration is decreased. Subsequently, we isolated several mutants affected in one or another of the mtDNA-encoded subunits of complex I by exposing established cell lines to high concentrations of rotenone. Our analyses of these mtDNA mutations affecting subunits of complex I have shown that at least two of these subunits, ND4 and ND6, are essential for the assembly of the enzyme. ND5 appears to be located at the periphery of the enzyme and, while it is not essential for assembly of the other mtDNA-encoded subunits into a complex, it is essential for complex I activity. In fact, the synthesis of the ND5 polypeptide is rate limiting for the activity of the enzyme. 相似文献
15.
Mitochondrial dysfunction and consequent energy depletion are the major causes of oxidative stress resulting to bring alterations in the ionic homeostasis causing loss of cellular integrity. Our previous studies have shown the age-associated interactive effects in rat central nervous system (CNS) upon co-exposure to chlorpyrifos (CPF) and cold stress leading to macromolecular oxidative damage. The present study elucidates a possible mechanism by which CPF and cold stress interaction cause(s) mitochondrial dysfunction in an age-related manner. In this study, the activity levels of Krebs cycle enzymes and electron transport chain (ETC) protein complexes were assessed in the isolated fraction of mitochondria. CPF and cold stress (15 and 20 °C) exposure either individually or in combination decreased the activity level of Krebs cycle enzymes and ETC protein complexes in discrete regions of rat CNS. The findings confirm that cold stress produces significant synergistic effect in CPF intoxicated aging rats. The synergism between CPF and cold stress at 15 °C caused a higher depletion of respiratory enzymes in comparison with CPF and cold stress alone and together at 20 °C indicating the extent of deleterious functional alterations in discrete regions of brain and spinal cord (SC) which may result in neurodegeneration and loss in neuronal metabolic control. Hence, co-exposure of CPF and cold stress is more dangerous than exposure of either alone. Among the discrete regions studied, the cerebellum and medulla oblongata appears to be the most susceptible regions when compared to cortex and SC. Furthermore, the study reveals a gradual decrease in sensitivity to CPF toxicity as the rat matures. 相似文献
16.
NO Synthase and NO-Dependent Signal Pathways in Brain Aging and Neurodegenerative Disorders: The Role of Oxidant/Antioxidant Balance 总被引:12,自引:0,他引:12
Nitric oxide and other reactive nitrogen species appear to play several crucial roles in the brain. These include physiological processes such as neuromodulation, neurotransmission and synaptic plasticity, and pathological processes such as neurodegeneration and neuroinflammation. There is increasing evidence that glial cells in the central nervous system can produce nitric oxide in vivo in response to stimulation by cytokines and that this production is mediated by the inducible isoform of nitric oxide synthase. Although the etiology and pathogenesis of the major neurodegenerative and neuroinflammatory disorders (Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis) are unknown, numerous recent studies strongly suggest that reactive nitrogen species play an important role. Furthermore, these species are probably involved in brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. Recent evidence also indicates the importance of cytoprotective proteins such as heat shock proteins (HSPs) which appear to be critically involved in protection from nitrosative and oxidative stress. In this review, evidence for the involvement of nitrosative stress in the pathogenesis of the major neurodegenerative/ neuroinflammatory diseases and the mechanisms operating in brain as a response to imbalance in the oxidant/antioxidant status are discussed. 相似文献
17.
Previous studies have shown that caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat organs, which can be linked to the slowing of aging rate induced by this regime. These two characteristics are also typical of long-lived animals. However, it has never been investigated if those decreases are linked to the decrease in the intake of calories themselves or to decreases in specific dietary components. In this study the possible role of the dietary protein was investigated. Using semipurified diets, the ingestion of proteins of Wistar rats was decreased by 40% below that of controls while the other dietary components were ingested at the same level as in animals fed ad libitum. After seven weeks in this regime the liver of the protein restricted animals showed 30–40% decreases in mitochondrial production of reactive oxygen species (ROS) and in oxidative damage to nuclear and mitochondrial DNA. The decreases in ROS generation occurred specifically at complex~I. They also occurred without changes in mitochondrial oxygen consumption. Instead, there was a decrease in the percent free radical leak (the percentage of total electron flow leading to ROS generation in the respiratory chain). These results are strikingly similar to those previously obtained after 40% caloric restriction in the liver of Wistar rats. Thus, the results suggest that part of the decrease in aging rate induced by caloric restriction can be due to the decreased intake of proteins acting through decreases in mitochondrial ROS production and oxidative DNA damage. Interestingly, these tissue oxidative stress-linked parameters can be lowered by restricting only the intake of dietary protein, probably a more feasible option than caloric restriction for adult humans. 相似文献
18.
R. Lodi B. Rajagopalan J.L. Bradley D.J. Taylor J.G. Crilley P.E. Hart 《Free radical research》2013,47(4):461-466
Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q 10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials. 相似文献
19.
An age-related Ca(2+) dysregulation and increased production of reactive oxygen species (ROS) may contribute to late-onset neurodegenerative disorders. These alterations are often attributed to impaired mitochondrial function yet few studies have directly examined mitochondria isolated from various regions of the aged brain. The purpose of this study was to examine Ca(2+)-buffering and ROS production in mitochondria isolated from Fischer 344 rats ranging in age from 4 to 25 months. Mitchondria isolated from the cortex of the 25 month rat brain exhibited greater rates of ROS production and mitochondrial swelling in response to increasing Ca(2+) loads as compared to mitochondria isolated from younger (4, 13 month) animals. The increased swelling is indicative of opening of the mitochondrial permeability transition pore indicating impaired Ca(2+) buffering/cycling in aged animals. These age-related differences were not observed in mitochondria isolated from cerebellum. Together, these results demonstrate region specific, age-related, alterations in mitochondrial responses to Ca(2+). 相似文献
20.
Matthew E. Talbert Brittany Barnett Robert Hoff Maria Amella Kate Kuczynski Erik Lavington Spencer Koury Evgeny Brud Walter F. Eanes 《Proceedings. Biological sciences / The Royal Society》2015,282(1815)
There is a connection between nutrient inputs, energy-sensing pathways, lifespan variation and aging. Despite the role of metabolic enzymes in energy homeostasis and their metabolites as nutrient signals, little is known about how their gene expression impacts lifespan. In this report, we use P-element mutagenesis in Drosophila to study the effect on lifespan of reductions in expression of seven central metabolic enzymes, and contrast the effects on normal diet and dietary restriction. The major observation is that for five of seven genes, the reduction of gene expression extends lifespan on one or both diets. Two genes are involved in redox balance, and we observe that lower activity genotypes significantly extend lifespan. The hexokinases also show extension of lifespan with reduced gene activity. Since both affect the ATP/ADP ratio, this connects with the role of AMP-activated protein kinase as an energy sensor in regulating lifespan and mediating caloric restriction. These genes possess significant expression variation in natural populations, and our experimental genotypes span this level of natural activity variation. Our studies link the readout of energy state with the perturbation of the genes of central metabolism and demonstrate their effect on lifespan. 相似文献