Mutation Research/DNAging最新文献

{"title":"Deleterious mitochondrial DNA mutations accumulate in aging human tissues","authors":"Norman Arnheim,&nbsp;Gino Cortopassi","doi":"10.1016/0921-8734(92)90020-P","DOIUrl":"10.1016/0921-8734(92)90020-P","url":null,"abstract":"<div><p>This paper reviews the current state of knowledge of the contribution of mitochondrial DNA (mtDNA) mutations to the phenotype of aging. Its major focus is on the discovery of deletions of mtDNA which previously were thought to occur only in individuals with neuromuscular disease. One particular deletion (mtDNA⁴⁹⁷⁷) accumulates with age primarily in non-dividing cells such as muscle and brain of normal individuals. The level of the deletion rises with age by more than 1000 fold in heart and brain and to a lesser extent in other tissues. In the brain, different regions have substantially different levels of the deletion. High levels of accumulation of the deletion in tissues are correlated with high oxygen consumption. We speculate that oxidative damage to mtDNA may be ‘catastrophic’; mutations affecting mitochondrially encoded polypeptides involved in electron transport could increase free radical generation leading to more mtDNA damage.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90020-P","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12555431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural dynamics of the mitochondrial compartment","authors":"Peter E. Thorsness","doi":"10.1016/0921-8734(92)90027-M","DOIUrl":"10.1016/0921-8734(92)90027-M","url":null,"abstract":"<div><p>The metabolic activities of mitochondria have been extensively characterized. However, there is much less known about the morphogenic changes of the mitochondrial compartment during growth, development and aging of the cell and the consequences of those structural changes on cellular metabolism. There is a growing body of evidence for interactions of mitochondria with cytoskeletal components and changes of mitochondrial structure during development and in response to charging environmental conditions. Segregation and recombination of mitochondrial genomes are also processes dependent upon the dynamic nature of the mitochondrial compartment. These regulatory and structural aspects of mitochondrial compartment dynamics will play an important role in the analysis of mitochondrial function and pathology.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90027-M","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12556526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Singlet oxygen induced DNA damage","authors":"Helmut Sies ,&nbsp;Carlos F.M. Menck","doi":"10.1016/0921-8734(92)90039-R","DOIUrl":"10.1016/0921-8734(92)90039-R","url":null,"abstract":"<div><p>Singlet oxygen generated by photoexcitation and by chemiexcitation selectively reacts with the guanine moiety in nucleosides (k_q + k_r about 5 x 10⁶ M⁻¹s⁻¹) and in DNA. The oxidation products include 8-oxo-7-hydro-deoxyguanosine (8-oxodG; also called 8-hydroxydeoxyguanosine) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine ( (FapyGua). Singlet oxygen also causes alkali-labile sites and single-strand breaks in DNA. The biological consequences include a loss of transforming activity as studied with plasmids and bacteriophage DNA, and mutagenicity and genotoxicity. Employing shuttle vectors, it was shown that double-stranded vectors carrying singlet oxygen induced lesions seem to be processed in mammalian cells by DNA repair mechanisms efficient in preserving the biological activity of the plasmid but highly mutagenic in mammalian cells. Biological protection against singlet oxygen is afforded by quenchers, notably carotenoids and tocopherols. Major repair occurs by excision of the oxidized deoxyguanosine moieties by the Fpg protein, preventing mismatch of 8-oxodG with dA, which would generate G:C to T:A transversions.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90039-R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12556944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell culture models for oxidative stress: superoxide and hydrogen peroxide versus normobaric hyperoxia","authors":"J.J.P. Gille,&nbsp;H. Joenje","doi":"10.1016/0921-8734(92)90043-O","DOIUrl":"10.1016/0921-8734(92)90043-O","url":null,"abstract":"<div><p>According to the free radical theory of aging, loss of cellular function during aging is a consequence of accumulating subcellular damage inflicted by activated oxygen species. In cells, the deleterious effects of activated oxygen species may become manifest when the balance between radical formation and destruction (removal) is disturbed creating a situation denoted as ‘oxidative stress’. Cell culture systems are especially useful to study the effects of oxidative stress, in terms of both toxicity and cellular adaptive responses. A better understanding of such processes may be pertinent to fully comprehend the cellular aging process.</p><p>This article reviews three model systems for oxidative stress: extracellular sources of O₂⁻ and H₂O₂, and normobaric hyperoxia (elevated ambient oxygen). Methodological and practical aspects of these exposure models are discussed, as well as their prominent effects as observed in cultures of Chinese hamster cell lines. Since chronic exposure models are to be preferred, it is argued that normobaric hyperoxia is a particularly relevant oxidative stress model for in vitro cellular aging studies.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90043-O","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12556948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progressive loss of cytochrome c oxidase in the human extraocular muscles in ageing — a cytochemical-immunohistochemical study","authors":"J. Müller-Höcker ,&nbsp;K. Schneiderbanger ,&nbsp;F.H. Stefani ,&nbsp;B. Kadenbach","doi":"10.1016/0921-8734(92)90016-I","DOIUrl":"10.1016/0921-8734(92)90016-I","url":null,"abstract":"<div><p>Cytochrome <em>c</em> oxidase (complex IV of the respiratory chain) was studied histochemically in autoptic human extraocular muscles (n = 135), reaveling randomly distributed single fibers without enzyme activity. The enzyme defect was expressed in all the mitochondria of an involved fiber as evidenced by ultracytochemistry. Succinate dehydrogenase showed normal histochemical reactivity.</p><p>The defects occured already in the second decade and were regularly seen from the third decade on. The defect density (defects/mm²)increased from approx. 1/mm² below The fifth decade to about 4/mm² in advanced age (<em>P</em> = 0.000). The highest defect density was observed in the levator palpebrae muscle. On the whole, the defect density was about 5–6 times higher in the extraocular muscles than in the limb muscle, diaphragm and heart (Müller-Höcker, 1989, 1990).</p><p>Immunocytochemical detection of cytochrome <em>c</em> oxidase showed that loss of cytochrome <em>c</em> oxidase activity was due to an almost complete absence of both nuclear and mitochondria subunits of the enzyme.</p><p>The results document different organ and heterogeneic cellular sensitivity to the age-related loss of cytochrome <em>c</em> oxidase. The loss of both mitochondrial and nuclear subunits indicates that nuclear factors are most probably involved in the decline of the respiratory chain function in senescence.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90016-I","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12555427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Free radical theory of aging","authors":"Denham Harman","doi":"10.1016/0921-8734(92)90030-S","DOIUrl":"10.1016/0921-8734(92)90030-S","url":null,"abstract":"<div><p>Free radical reactions are ubiquitous in living things. Studies on the origin and evolution of life provide a reasonable explanation for the prominent presence of this unruly class of chemical reactions. These reactions have been implicated in aging. This phenomenon is the accumulation of changes responsible for the sequential alterations that accompany advancing age and the associated progressive increases in the chance of disease and death. Aging changes are attributed to the environment and disease, and to an inborn process, the aging process. The latter produces aging changes at an exponentially increasing rate with advancing age. Past improvements in general living conditions have decreased the chances for death so that they are now near limiting values in the developed countries. In these countries the intrinsic aging process in the major cause of disease and death after about age 28. The free radical theory of aging postulates that aging changes are caused by free radical reactions. The data supporting this theory indicate that average life expectancy at birth may be increased by 5 or more years, by nutritious low caloric diets supplemented with one or more free radical reaction inhibitors.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90030-S","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12555830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial DNA mutation and the ageing process: bioenergy and pharmacological intervention","authors":"Anthony W. Linnane,&nbsp;Chunfang Zhang,&nbsp;Alessandra Baumer,&nbsp;Phillip Nagley","doi":"10.1016/0921-8734(92)90023-I","DOIUrl":"10.1016/0921-8734(92)90023-I","url":null,"abstract":"<div><p>A comprehensive hypothesis concerning the contribution of mitochondrial DNA (mtDNA) mutations to the human ageing process is reviewed and the implications for cellular bioenergy loss and pharmacological therapy are considered. The central idea is that random mutations in the population of mtDNA molecules of each cell occur throughout life, and that this is a major contributor to the gradual loss of cellular bioenergy capacity within tissues and organs, associated with general senescence and diseases of ageing. An elaboration of four major aspects fo the general proposition, together with relevant supporting data, is presented. (1) An extensive array of deletions in mtDNA of many tissues of humans and other mammals has been observed to occur in an age-related manner. (2) The preservation and selection of fully functional mtDNA molecules in the female germ line cells is proposed to occur via a human mtDNA cycle, in which selective amplification of a limited number of mtDNA templates occurs during oocyte development. This proposal explains the endowment of normal neonates with mtDNA complement minimally contaminated by damaged mtDNA molecules. The phenomena of maternal inheritance and rapid fixation of sequence variants of mtDNA in mammals, as well as selection of cells based on mitochondrial function, are taken into account. (3) Tissue bioenergy mosaics result from accumulated mtDNA damage during ageing, representing different rates of cellular bioenergy loss within individual cells of a tissue. The random segregation of mtDNA during cell division will also further contribute to the tissue energy mosaic. Cells unable to meet their particular bioenergy demand will become non-functional, leading to cell death; the bioenergy threshold is different for the various cell types in the tissues of the body. (4) In order to bioenergetically resuscitate cells and tissues suffering from impaired mitochondrial functions as a result of the ageing process, we prpopse that redox compounds may be used therapeutically in the pharmacological configurations of a by-pass strategy or as a redox sink therapy. The role of these compounds is to maintain at least part of the mitochondrial respiratory chain function (by-pass) as well as to maintain adequate levels of cellular NAD⁺ (redox sink) for ATP synthesis, predominantly by the cytosolic glycolytic pathway, with some contribution from mitochondrial oxidative phosphorylation.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90023-I","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12556522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel hypothesis of lipofuscinogenesis and cellular aging based on interactions between oxidative stress and autophagocytosis","authors":"Ulf T. Brunk ,&nbsp;Charles B. Jones ,&nbsp;Rajindar S. Sohal","doi":"10.1016/0921-8734(92)90042-N","DOIUrl":"10.1016/0921-8734(92)90042-N","url":null,"abstract":"<div><p>Based on a series of experiments, using cultured postmitotic neonatal rat cardiac myocytes as a model system, we present a novel hypothesis of lipofuscin formation. This hypothesis proposes that lipofuscin is formed within secondary lysosomes due to an interplay of two processes, the production of partially reduced oxygen species by mitochondria and the autophagocytotic degradation within secondary lysosomes. Specifically, it is proposed that H₂O₂ generated by mitochondria and other organelles permeates into the lumen of secondary lysosomes, which contain iron derived from cellular structures undergoing intralysosomal degradation. The interaction between reactive ferrous iron and H₂O₂ results, via Fenton-type mechanisms, in the generation of hydroxyl free radicals (OH), inducing lipid peroxidation and eventually leading to intermolecular cross-linking and lipofuscin formation. Additionally, mitochondria undergoing intralysosomal decomposition might continue for a certain period to produce superoxide anion radicals (O₂⁻) and thus also H₂O₂. This model of lipofuscinogenesis could satisfactorily explain the variations observed in the rates of lipofuscinogenesis among different postmitotic cell types in various species. Such variations might arise from a variety of factors including differences in the efficiency of the ‘anti-oxidative shield’, rate of H₂O₂ generation, amount of chain-breaking antioxidants, mode of intralysosomal iron chelation, rate of autophagocytosis as well as degree of efficiency of the intralysosomal hydrolytic enzymes.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90042-N","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12556947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial function in neurodegeneration and ageing","authors":"A.H.V. Schapira ,&nbsp;J.M. Cooper","doi":"10.1016/0921-8734(92)90018-K","DOIUrl":"10.1016/0921-8734(92)90018-K","url":null,"abstract":"<div><p>The mitochondrial respiratory chain and oxidative phosphorylation system are responsible for the production of ATP by aerobic metabolism. Defects of the respiratory chain are increasingly recognised as important causes of human disease, and neurodegenerative disorders in particular. This article will seek to review the clinical and biochemical effects of respiratory chain defects, and summarise what is known about the molecular mechanisms that underlie them. Increasing age is also associated with a decline in mitochondrial function. The biochemical correlates of this dysfunction and the possible molecular defects that may cause it will also be reviewed.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90018-K","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12555429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial production of pro-oxidants and cellular senescence","authors":"R.S. Sohal ,&nbsp;U.T. Brunk","doi":"10.1016/0921-8734(92)90033-L","DOIUrl":"10.1016/0921-8734(92)90033-L","url":null,"abstract":"<div><p>Mitochondria are the major intracellular producers of O₂⁻ and H₂O₂. The level of oxidative stress in cells, as indicated by the in vivo exhalation of alkanes and the concentration of molecular products of oxy-radical reactions, increases during aging in mammals as well as insects. In this paper, we discuss the relationship between mitochondrial generaton of O₂⁻ and H₂O₂, and the aging process. The rate of mitochondrial O₂⁻ and H₂O₂ generation increases with age in houselifes and the brain, heart and liver of rat. This rate has been found to correspond to the life expectancy of flies to the maximum life span potential (MLSP) of six different mammalian species, namely, mouse, rat, guinea pig, rabbit, pig and cow. In contrast, the level of antioxidant defenses provided by activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione concentration neither uniformly declines with age nor corresponds to variations in MLSP of different mammalian species. It is argued that the rate of mitochondrial O₂⁻ and H₂O₂ generation rather than the antioxidant level may act as a longevity determinant.</p></div>","PeriodicalId":100937,"journal":{"name":"Mutation Research/DNAging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0921-8734(92)90033-L","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12555833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}