Free radical processes in aging, neurodegenerative diseases and other pathological states

Literature data on the role of oxidative stress in aging have been summarized. There are certain links between parameters of free radical processes (intensity of generation of reactive oxygen species in mitochondria, oxidative modification of mitochondrial DNA, activity of desaturases, involved into biosynthesis of polyunsaturated C₂₀ and C₂₂ fatty acids) with life span. The review highlights the role of oxidative stress as on of pathogenic factors of numerous diseases including various neurodegenerative disorders. Special attention is paid to oxidative modification of proteins as one of early and reliable markers of tissue injury in free radical pathology. Oxidative destruction of proteins plays a major role in etiology of such neurodegenerative diseases as Alzheimer’s and Parkinson’s diseases. Oxidative stress and the stress related protein aggregation are considered as the pathogenic link in the development of familiar amyotrophic lateral sclerosis. Oxidative modification of proteins is associated with the development of cataract. The age-and pathology-related increases in the content of oxidized proteins in tissues is assessed as an early and specific parameter of oxidative stress.     

Roles of sirtuins in the regulation of antioxidant defense and bioenergetic function of mitochondria under oxidative stress

Abstract

In addition to serving as the power house of mammalian cells, mitochondria are crucial for the maintenance of cellular homeostasis in response to physiological or environmental changes. Several lines of evidence suggest that posttranslational modification (PTM) of proteins plays a pivotal role in the regulation of the bioenergetic function of mitochondria. Among them, reversible lysine acetylation of mitochondrial proteins has been established as one of the key mechanisms in cellular response to energy demand by modulating the flux of a number of key metabolic pathways. In this article, we focus on the role of Sirt3-mediated deacetylation in: (1) flexibility of energy metabolism, (2) activation of antioxidant defense, and (3) maintenance of cellular redox status in response to dietary challenge and oxidative stress. We suggest that oxidative stress-elicited down-regulation of Sirt3 plays a role in the pathophysiology of diabetes, cardiac hypotrophy, mitochondrial diseases, and age-related diseases. Besides, the physiological role of newly identified lysine acylation mediated by Sirt5 and its biochemical effects on oxidative metabolism are also discussed. Moreover, we have integrated the regulatory function of several protein kinases that are involved in the phosphorylation of mitochondrial enzymes during oxidative stress. Finally, the functional consequence of the synergistic regulation through diverse protein modifications is emphasized on the maintenance of the bioenergetic homeostasis and metabolic adaptation of the animal and human cells. Together, we have provided an updated review of PTM in mitochondrial biology and their implications in aging and human diseases through an intricate regulation of energy metabolism under oxidative stress.     

空气污染与神经退行性疾病

随着现代社会工业的发展,空气污染日益严重,空气污染对人体的损害也越来越大。空气污染中的有害物质,能通过各种途径引起各系统的疾病,甚至会影响儿童的身体和智力发育。研究发现,长期暴露或急性暴露在某些空气污染物中可以直接损伤中枢神经系统,或污染物引起呼吸系统和免疫系统等产生有害因子,通过外周循环到达大脑,导致大脑的神经炎症、神经毒性、氧化应激等反应,最终产生神经退行性病变,如阿尔茨海默病（Alzheimer’s disease,AD）、帕金森病（Parkinson’s disease,PD）等。     

Mitochondrial metabolism of reactive oxygen species

Oxidative stress is considered a major contributor to etiology of both normal senescence and severe pathologies with serious public health implications. Mitochondria generate reactive oxygen species (ROS) that are thought to augment intracellular oxidative stress. Mitochondria possess at least nine known sites that are capable of generating superoxide anion, a progenitor ROS. Mitochondria also possess numerous ROS defense systems that are much less studied. Studies of the last three decades shed light on many important mechanistic details of mitochondrial ROS production, but the bigger picture remains obscure. This review summarizes the current knowledge about major components involved in mitochondrial ROS metabolism and factors that regulate ROS generation and removal. An integrative, systemic approach is applied to analysis of mitochondrial ROS metabolism, which is now dissected into mitochondrial ROS production, mitochondrial ROS removal, and mitochondrial ROS emission. It is suggested that mitochondria augment intracellular oxidative stress due primarily to failure of their ROS removal systems, whereas the role of mitochondrial ROS emission is yet to be determined and a net increase in mitochondrial ROS production in situ remains to be demonstrated.Translated from Biokhimiya, Vol. 70, No. 2, 2005, pp. 246–264.Original Russian Text Copyright © 2005 by Andreyev, Kushnareva, Starkov.This revised version was published online in April 2005 with corrections to the post codes.     

氧化应激对肠屏障功能障碍发病的影响

机体累积过量的活性氧自由基所导致的氧化应激是多种肠道疾病发生的共同病理生理基础。肠上皮细胞间的紧密连接是维持肠屏障功能的重要结构基础之一。近年来研究表明,氧化应激能通过多种途径破坏肠上皮细胞间的紧密连接,导致肠上皮屏障功能障碍。本文对蛋白激酶C、丝裂原活化蛋白激酶、蛋白质的修饰以及缺氧诱导因子-1(HIF-1)在肠屏障功能障碍中的作用机制进行简要概述,旨在为肠屏障功能障碍的治疗和预后提供新的思路。     

氧化应激相关性疾病中线粒体机制的研究进展

氧化应激是由体内生成的活性氧（reactive oxygen species,ROS）／活性氮（reactivenitro．genspecies,RNS）与抗氧化防御机制之间的平衡被打破引起的,这与许多疾病的发病机理相关,包括神经退行性病变、肿瘤、炎症性疾病等。而线粒体作为细胞代谢的中枢,是其作用的主要靶细胞器,氧化应激引起线粒体内脂质、蛋白质与核酸的损伤,导致线粒体结构和功能的改变,该文就线粒体在上述与氧化应激相关的疾病中改变的研究进展作一综述。     

The role of endothelial dysfunction and oxidative stress in cerebrovascular diseases

Cerebrovascular diseases (CBD) are one of the most dangerous complications of atherosclerosis. The clinical consequences of CBD deeply impact quality of life and the prognosis of patients. Atherosclerosis is the main cause of CBD development. Hypertension, dyslipidemia, diabetes, smoking, obesity, and other risk factors explain the higher CBD incidence in the general population, as they are able to anticipate the clinical expression of atherosclerosis. These risk factors are effectively able to promote endothelial dysfunction which is the premise for the early, clinical expression of atherosclerosis. The mechanisms by which risk factors can influence the occurrence of CBD are different and not fully understood. The inflammatory background of atherosclerosis can explain a great part of it. In particular, the oxidative stress may promote the development of vascular lesions by negatively influencing biochemical cellular processes of the endothelium, thus predisposing the vascular tree to morphological and functional damages. The aim of this narrative review is to evaluate the role of endothelial dysfunction and oxidative stress in CBD development.     

Carotenoids, oxidative stress and female mating preference for longer lived males

Some of the most spectacular exaggerated sexual ornaments are carotenoid dependent. It has been suggested that such ornaments have evolved because carotenoid pigments are limiting for both signal expression and in their role as antioxidants and immunostimulants. An implicit assumption of this hypothesis is that males which can afford to produce more elaborate carotenoid-dependent displays are signalling their enhanced ability to resist parasites, disease or oxidative stress and hence would be predicted to live longer. Therefore, in species with carotenoid-dependent ornaments where a parent's future longevity is crucial for determining offspring survival, there should be a mating preference for partners that present the lowest risk of mortality during the breeding attempt, as signalled by the ability to allocate carotenoids to sexual displays. In an experimental study using three-spined sticklebacks (Gasterosteus aculeatus), we show that when dietary carotenoid intake is limited, males attempt to maintain their sexual ornament at the expense of body carotenoids and hence suffer from reduced reproductive investment and a shorter lifespan. These males also suffer from an increased susceptibility to oxidative stress, suggesting that this may constitute the mechanism underlying the increased rate of ageing. Furthermore, in pairwise mate-choice trials, females preferred males that had a greater access to carotenoids and chance of surviving the breeding season, suggesting that females can make adaptive mate choice decisions based on a male's carotenoid status and potential future longevity.     

Changes in the antigenic properties of proteins of laboratory mice during oxidative stress

Changes in the level of oxidative damage to proteins in CD1 outbred mice γ irradiated with a dose of 3 Gy have been studied. The changes were estimated from the amount of carbonyl groups (CG) in the proteins. It was found that two hours after exposure to γ radiation, the amount of CG in the cytoplasmic and nuclear fractions of the liver, heart, brain, and spleen sharply increased. Two months after irradiation, the level of CG in the cytoplasmic and nuclear subcellular fractions of the liver and brain decreased to the level of CG in the control animals, which were not exposed to radiation. In the subcellular fractions of the heart and spleen, the increase in the degree of damage was more significant and a high level of damage was observed even two months after irradiation. An enhancement of the antigenic properties of proteins from the liver, heart, and spleen in the postirradiation period was found. Spleen proteins were most immunogenic. A comparison of the antigenic properties of proteins isolated from the tissues 60 days after irradiation revealed a correlation between the level of oxidative damage and the immunogenicity of the total protein fraction.     

Mitochondrial reticulum network dynamics in relation to oxidative stress, redox regulation, and hypoxia

A single mitochondrial network in the cell undergoes constant fission and fusion primarily depending on the local GTP gradients and the mitochondrial energetics. Here we overview the main properties and regulation of pro-fusion and pro-fission mitodynamins, i.e. dynamins-related GTPases responsible for mitochondrial shape-forming, such as pro-fusion mitofusins MFN1, MFN2, and the inner membrane-residing long OPA1 isoforms, and pro-fission mitodynamins FIS1, MFF, and DRP1 multimers required for scission. Notably, the OPA1 cleavage into non-functional short isoforms at a diminished ATP level (collapsed membrane potential) and the DRP1 recruitment upon phosphorylation by various kinases are overviewed. Possible responses of mitodynamins to the oxidative stress, hypoxia, and concomitant mtDNA mutations are also discussed. We hypothesize that the increased GTP formation within the Krebs cycle followed by the GTP export via the ADP/ATP carrier shift the balance between fission and fusion towards fusion by activating the GTPase domain of OPA1 located in the peripheral intermembrane space (PIMS). Since the protein milieu of PIMS is kept at the prevailing oxidized redox potential by the TOM, MIA40 and ALR/Erv1 import-redox trapping system, redox regulations shift the protein environment of PIMS to a more reduced state due to the higher substrate load and increased respiration. A higher cytochrome c turnover rate may prevent electron transfer from ALR/Erv1 to cytochrome c. Nevertheless, the putative links between the mitodynamin responses, mitochondrial morphology and the changes in the mitochondrial bioenergetics, superoxide production, and hypoxia are yet to be elucidated, including the precise basis for signaling by the mitochondrion-derived vesicles.     

Proteomic analysis of mitochondrial dysfunction in neurodegenerative diseases

Alzheimer’s, Parkinson’s and Huntington’s disease, and amyotrophic lateral sclerosis are the most relevant neurodegenerative syndromes worldwide. The identification of the etiology and additional factors contributing to the onset and progression of these diseases is of great importance in order to develop both preventive and therapeutic intervention. A common feature of these pathologies is the formation of aggregates, containing mutated and/or misfolded proteins, in specific subsets of neurons, which progressively undergo functional impairment and die. The relationship between protein aggregation and the molecular events leading to neurodegeneration has not yet been clarified. In the last decade, several lines of evidence pointed to a major role for mitochondrial dysfunction in the onset of these pathologies. Here, we review how proteomics has been applied to neurodegenerative diseases in order to characterize the relationship existing between protein aggregation and mitochondrial alterations. Moreover, we highlight recent advances in the use of proteomics to identify protein modifications caused by oxidative stress. Future developments in this field are expected to significantly contribute to the full comprehension of the molecular mechanisms at the heart of neurodegeneration.     

Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction

Oxidative stress is one of the earliest events in Alzheimer's disease (AD). A chemical genetic screen revealed that deregulated cyclin-dependent kinase 5 (Cdk5) may cause oxidative stress by compromising the cellular anti-oxidant defense system. Using novel Cdk5 modulators, we show the mechanism by which Cdk5 can induce oxidative stress in the disease's early stage and cell death in the late stage. Cdk5 dysregulation upon neurotoxic insults results in reactive oxygen species (ROS) accumulation in neuronal cells because of the inactivation of peroxiredoxin I and II. Sole temporal activation of Cdk5 also increases ROS, suggesting its major role in this process. Cdk5 inhibition rescues mitochondrial damage upon neurotoxic insults, thereby revealing Cdk5 as an upstream regulator of mitochondrial dysfunction. As mitochondrial damage results in elevated ROS and Ca(2+) levels, both of which activate Cdk5, we propose that a feedback loop occurs in late stage of AD and leads to cell death (active Cdk5 --> ROS --> excess ROS --> mitochondrial damage --> ROS --> hyperactive Cdk5 --> severe oxidative stress and cell injury --> cell death). Cdk5 inhibition upon neurotoxic insult prevents cell death significantly, supporting this hypothesis. As oxidative stress and mitochondrial dysfunction play pivotal roles in promoting neurodegeneration, Cdk5 could be a viable therapeutic target for AD.     

Glucose,glycolysis, and neurodegenerative diseases

Prolonged survival of a typical postmitotic neuron hinges on a balance between multiple processes, among these are a sustenance of ATP production and protection against reactive oxygen species. In neuropathological conditions, mitochondrial defects often lead to both a drop in ATP levels, as well as increase reactive oxygen species production from inefficient electron transport processes and NADPH-oxidases activities. The former often resulted in the phenomenon of compensatory aerobic glycolysis. The latter stretches the capacity of the cell's redox buffering capacity, and may lead to damages of key enzymes involved in energy metabolism. Several recent reports have indicated that enhancing glucose availability and uptake, as well as increasing glycolytic flux via pharmacological or genetic manipulation of glycolytic enzymes, could be protective in animal models of several major neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Activation of canonical Wnt signaling, which improves disease symptoms in mouse models of Alzheimer's disease also appears to work via an elevation of glycolytic enzymes and enhance glucose metabolism. Here, I discuss these findings and the possible underlying mechanisms of how an increase in glucose uptake and glycolysis could be neuroprotective. Increased glycolytic production of ATP would help alleviate energy deficiency, and ATP's hydrotropic effect may enhance solubility and clearance of toxic aggregates prevalent in many neurodegenerative diseases. Furthermore, channeling of glucose into the Pentose Phosphate Pathway would increase the redox buffering capacity of the cell.     

New strategy of bone marrow mesenchymal stem cells against oxidative stress injury via Nrf2 pathway: oxidative stress preconditioning

Clinically, bone marrow mesenchymal stem cells (BMSCs) have been used in treatment of many diseases, but the local oxidative stress (OS) of lesion severely limits the survival of BMSCs, which reduces the efficacy of BMSCs transplantation. Therefore, enhancing the anti-OS stress ability of BMSCs is a key breakthrough point. Preconditioning is a common protective mechanism for cells or body. Here, the aim of this study was to investigate the effects of OS preconditioning on the anti-OS ability of BMSCs and its mechanism. Fortunately, OS preconditioning can increase the expression of superoxide dismutase, catalase, NQO1, and heme oxygenase 1 through the nuclear factor erythroid 2-related factor 2 pathway, thereby decreased the intracellular reactive oxygen species (ROS) levels, relieved the damage of ROS to mitochondria, DNA and cell membrane, enhanced the anti-OS ability of BMSCs, and promoted the survival of BMSCs under OS.