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1
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Role of cellular senescence in inflammatory lung diseases. Cytokine Growth Factor Rev 2023; 70:26-40. [PMID: 36797117 DOI: 10.1016/j.cytogfr.2023.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/05/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023]
Abstract
Cellular senescence, a characteristic sign of aging, classically refers to permanent cell proliferation arrest and is a vital contributor to the pathogenesis of cancer and age-related illnesses. A lot of imperative scientific research has shown that senescent cell aggregation and the release of senescence-associated secretory phenotype (SASP) components can cause lung inflammatory diseases as well. In this study, the most recent scientific progress on cellular senescence and phenotypes was reviewed, including their impact on lung inflammation and the contributions of these findings to understanding the underlying mechanisms and clinical relevance of cell and developmental biology. Within a dozen pro-senescent stimuli, the irreparable DNA damage, oxidative stress, and telomere erosion are all crucial in the long-term accumulation of senescent cells, resulting in sustained inflammatory stress activation in the respiratory system. An emerging role for cellular senescence in inflammatory lung diseases was proposed in this review, followed by the identification of the main ambiguities, thus further understanding this event and the potential to control cellular senescence and pro-inflammatory response activation. In addition, novel therapeutic strategies for the modulation of cellular senescence that might help to attenuate inflammatory lung conditions and improve disease outcomes were also presented in this research.
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2
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Faniyi AA, Hughes MJ, Scott A, Belchamber KBR, Sapey E. Inflammation, Ageing and Diseases of the Lung: Potential therapeutic strategies from shared biological pathways. Br J Pharmacol 2021; 179:1790-1807. [PMID: 34826882 DOI: 10.1111/bph.15759] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 10/07/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Lung diseases disproportionately affect elderly individuals. The lungs form a unique environment: a highly elastic organ with gaseous exchange requiring the closest proximity of inhaled air containing harmful agents and the circulating blood volume. The lungs are highly susceptible to senescence, with age and "inflammageing" creating a pro-inflammatory environment with a reduced capacity to deal with challenges. Whilst lung diseases may have disparate causes, the burden of ageing and inflammation provides a common process which can exacerbate seemingly unrelated pathologies. However, these shared pathways may also provide a common route to treatment, with increased interest in drugs which target ageing processes across respiratory diseases. In this review, we will examine the evidence for the increased burden of lung disease in older adults, the structural and functional changes seen with advancing age and assess what our expanding knowledge of inflammation and ageing pathways could mean for the treatment of lung disease.
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Affiliation(s)
- A A Faniyi
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - M J Hughes
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - A Scott
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - K B R Belchamber
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
| | - E Sapey
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, U.K
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3
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Schiffers C, Reynaert NL, Wouters EFM, van der Vliet A. Redox Dysregulation in Aging and COPD: Role of NOX Enzymes and Implications for Antioxidant Strategies. Antioxidants (Basel) 2021; 10:antiox10111799. [PMID: 34829671 PMCID: PMC8615131 DOI: 10.3390/antiox10111799] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/04/2021] [Accepted: 11/06/2021] [Indexed: 12/23/2022] Open
Abstract
With a rapidly growing elderly human population, the incidence of age-related lung diseases such as chronic obstructive pulmonary disease (COPD) continues to rise. It is widely believed that reactive oxygen species (ROS) play an important role in ageing and in age-related disease, and approaches of antioxidant supplementation have been touted as useful strategies to mitigate age-related disease progression, although success of such strategies has been very limited to date. Involvement of ROS in ageing is largely attributed to mitochondrial dysfunction and impaired adaptive antioxidant responses. NADPH oxidase (NOX) enzymes represent an important enzyme family that generates ROS in a regulated fashion for purposes of oxidative host defense and redox-based signalling, however, the associations of NOX enzymes with lung ageing or age-related lung disease have to date only been minimally addressed. The present review will focus on our current understanding of the impact of ageing on NOX biology and its consequences for age-related lung disease, particularly COPD, and will also discuss the implications of altered NOX biology for current and future antioxidant-based strategies aimed at treating these diseases.
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Affiliation(s)
- Caspar Schiffers
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT 05405, USA; (C.S.); (E.F.M.W.)
- Ludwig Boltzmann Institute for Lung Health, 1140 Vienna, Austria
- Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6211 LK Maastricht, The Netherlands;
| | - Niki L. Reynaert
- Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6211 LK Maastricht, The Netherlands;
| | - Emiel F. M. Wouters
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT 05405, USA; (C.S.); (E.F.M.W.)
- Ludwig Boltzmann Institute for Lung Health, 1140 Vienna, Austria
- Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6211 LK Maastricht, The Netherlands;
| | - Albert van der Vliet
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT 05405, USA; (C.S.); (E.F.M.W.)
- Correspondence:
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Schneider JL, Rowe JH, Garcia-de-Alba C, Kim CF, Sharpe AH, Haigis MC. The aging lung: Physiology, disease, and immunity. Cell 2021; 184:1990-2019. [PMID: 33811810 PMCID: PMC8052295 DOI: 10.1016/j.cell.2021.03.005] [Citation(s) in RCA: 232] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/01/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023]
Abstract
The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.
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Affiliation(s)
- Jaime L Schneider
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Dana Farber Cancer Institute, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
| | - Jared H Rowe
- Division of Hematology Boston Children's Hospital and Division of Pediatric Oncology Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Carolina Garcia-de-Alba
- Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Carla F Kim
- Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
| | - Arlene H Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Disease, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
| | - Marcia C Haigis
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
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5
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Chen MJ, Shen CJ, Wang L, Chen PM, Chen CY, Lee H. Association of hOGG1-Cys variants with occurrence of p53 and EGFR deletion mutations in non-small cell lung cancer. Thorac Cancer 2020; 12:534-538. [PMID: 33372419 PMCID: PMC7882387 DOI: 10.1111/1759-7714.13799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 12/05/2022] Open
Abstract
Background The human 8‐oxoguanine DNA glycosylase 1 (hOGG1) gene encodes a DNA glycosylase that removes 8‐hydroxy‐2‐deoxyguanine (8‐OH‐dG) DNA damage to protect against gene mutations. The association of hOGG1 Ser326Cys polymorphism with lung cancer risk has predicted that hOGG1‐Cys variants are less effective at removing 8‐OH‐dG damage from DNA; therefore, these variants might show an increased occurrence of tumor suppressor gene and oncogene mutations. However, no evidence has yet supported this hypothesis. Methods Direct sequencing was performed to examine the mutations of p53 and EGFR genes in lung tumors from patients with non‐small cell lung cancer (NSCLC). Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used to examine hOGG1 Ser326Cys polymorphism in this study population. Results A total of 99 p53‐mutated and 99 EGFR‐mutated patients with NSCLC were selected to explore the possible associations of these mutations with hOGG1 Ser326Cys polymorphism. The p53‐mutated and EGFR‐mutated patients were divided into nondeletion and deletion subgroups. P53 deletion mutations were more commonly observed in male than in female patients (P = 0.030). However, EGFR exon 19 deletion mutations were more prevalent in female and adenocarcinoma patients than in male and squamous cell carcinoma patients (P = 0.028 for genders, P = 0.017 for tumor histology). Interestingly, p53 and EGFR exon 19 deletion mutations were more frequent in patients with hOGG1 Ser/Cys + Cys/Cys hOGG1‐Cys variants than with the hOGG1 Ser/Ser genotype (P = 0.010 for p53, P = 0.032 for EGFR). Conclusions We suggest that the association of hOGG1 Ser326Cys polymorphism with lung cancer risk could be partially explained by increases in p53 and EGFR deletion mutations. Key points Significant findings of the study
NSCLC patients with hOGG1‐Cys variants may have a higher risk of p53 and EGFR deletion mutations than with hOGG1 Ser/Ser genotype. What this study adds
NSCLC patients with hOGG1‐Cys variants might be helpful to predict patients having higher risk of EGFR exon 19 deletion mutations and these patients who were treated with gefitinib or erlotinib could be a higher risk to occur EGFR T790M mutation. NSCLC patients with hOGG1‐Cys variants may have higher risk of p53 and EGFR deletion mutations than with hOGG1 Ser/Ser genotype. NSCLC patients with hOGG1‐Cys variants might be helpful to predict patients with higher risk of EGFR exon 19 deletion mutations and these patients who were treated with gefitinib and erlotinib were more common to occur EGFR T790M mutation.
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Affiliation(s)
- Ming-Jenn Chen
- Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.,Department of Sports Management, College of Leisure and Recreation Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Ching-Ju Shen
- Department of Gynecology and Obstetrics, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Lee Wang
- Department of Public Heath, Chung Shan Medical University, Taichung, Taiwan
| | - Po-Ming Chen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Chih-Yi Chen
- Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Huei Lee
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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Abstract
Over the last decade, several theoretical models have been put forth to describe how animals respond to adverse environments and how this response changes under different physiological demands across life history stages. These models capture the context- and condition-dependent nature of stress responses. Yet, application of the models has been limited thus far in part because each model addresses different aspects of the problems facing the field of stress biology. Thus, there is a need for a unifying theoretical model that incorporates changes in physiological demand with life history stages and age, intricate relationships among physiological systems, and biphasic nature of stress responses. Here, I propose a new integrative framework, the Damage-Fitness Model. In this model, regulators, such as DNA repair mechanisms and glucocorticoids, work together as anti-damage mechanisms to minimize damage at both the cellular and organismal level. When the anti-damage regulators are insufficient or inappropriate, persistent damage accumulates. Previous studies indicate that these damage directly impact reproductive performance, disease risk, and survival. The types of regulators, the threshold at which they are initiated, and the magnitude of the responses are shaped by developmental and current environments. This model unites existing theoretical models by shifting our focus from physiological responses to downstream consequences of the stress responses, circumventing context specificity. Discussions include (1) how the proposed model relates to existing models, (2) steps to test the new model, and (3) how this model can be used to better assess the health of individuals and a population. Lay summary The field of stress physiology faces a challenge of characterizing dynamic cellular, physiological, and behavioral responses when animals encounter a stressor. This paper proposes a new theoretical model which links stress avoidance, damage repair and accumulation, and fitness components.
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Affiliation(s)
- Haruka Wada
- a Department of Biological Sciences, Auburn University , Auburn , AL , USA
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7
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Wang L, Ma S, Ding Q, Wang X, Chen Y. CRISPR/Cas9-mediated MSTN gene editing induced mitochondrial alterations in C2C12 myoblast cells. ELECTRON J BIOTECHN 2019. [DOI: 10.1016/j.ejbt.2019.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Afrifa J, Zhao T, Yu J. Circulating mitochondria DNA, a non-invasive cancer diagnostic biomarker candidate. Mitochondrion 2018; 47:238-243. [PMID: 30562607 DOI: 10.1016/j.mito.2018.12.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 11/05/2018] [Accepted: 12/14/2018] [Indexed: 12/15/2022]
Abstract
The mitochondria are defined by their unique structure and cellular functions which includes energy production, metabolic regulation, apoptosis, calcium homeostasis, cell proliferation, cell motility and transport as well as free radical generation. Recent advances geared towards enhancing the diagnostic and prognostic value of cancer patients have targeted the circulating mitochondria genome due to its specific and unique characteristics. Circulating mitochondria DNA is known to possess short length, relatively simple molecular structure and a high copy number. These coupled with its ability to serve as a liquid biopsy makes it an easily accessible non-invasive biomarker for diagnostics and prognostics of various forms of solid tumors. In this article, we review recent findings on circulating mitochondria DNA content in cancer. In addition, we provide an insight into the potential of circulating mitochondria DNA to act as a non-invasive diagnostic biomarker and its linearity with clinical and sociodemographic characteristics.
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Affiliation(s)
- Justice Afrifa
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Tie Zhao
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Jingcui Yu
- Scientific Research Centre, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
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Roman J, Zhu J, Ritzenthaler JD, Zelko IN. Epigenetic regulation of EC-SOD expression in aging lung fibroblasts: Role of histone acetylation. Free Radic Biol Med 2017; 112:212-223. [PMID: 28757400 DOI: 10.1016/j.freeradbiomed.2017.07.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 07/20/2017] [Accepted: 07/26/2017] [Indexed: 12/30/2022]
Abstract
Lung disorders characterized by fibroproliferation and excessive deposition of extracellular matrices occur in late adulthood, and their pathological manifestations become more prominent with aging. The exact mechanisms linking aging and fibroproliferative disorders are unknown, but increased oxidative stress resulting in the accumulation of damaged proteins, DNA, and lipids is considered a major factor. In the lung, and especially in the pulmonary fibroblasts, the extracellular superoxide dismutase (EC-SOD) is a major antioxidant enzyme that has been implicated in pulmonary fibrosing disorders, among others. Here, we investigate the regulation of EC-SOD in pulmonary lung fibroblasts derived from young (up to 3 month) and old (24 month) C57BL6 mice. We found that old fibroblasts have marginally elevated levels of reactive oxidant species (ROS), which coincides with attenuated expression a number of antioxidant enzymes including EC-SOD. Exposure of old fibroblasts to the DNA methyltransferase inhibitor 5-aza-dC did not restore expression of EC-SOD. On the other hand, repression of EC-SOD expression was associated with deacetylation of lysine 9 on histone H3 and lysines 5, 8, 12 and 16 on histone H4 located at the gene promoter. Interestingly, the repressive tri-methylation of lysine 27 on histone H3 was elevated in old compared to young fibroblasts. In addition, exposure of old lung fibroblasts to HDAC class 1 and class 2 inhibitors restored EC-SOD expression to the level observed in young fibroblasts. While the exact mechanism of age-dependent downregulation of EC-SOD is yet to be defined, our studies indicate a potential role of epigenetic mechanisms including histone deacetylation in this process.
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Affiliation(s)
- Jesse Roman
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY 40202, United States; Robley Rex VA Medical Center, Louisville, KY 40202, United States
| | - Jianxin Zhu
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY 40202, United States
| | - Jeffrey D Ritzenthaler
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY 40202, United States
| | - Igor N Zelko
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY 40202, United States; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, United States.
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Hsia CCW, Ravikumar P, Ye J. Acute lung injury complicating acute kidney injury: A model of endogenous αKlotho deficiency and distant organ dysfunction. Bone 2017; 100:100-109. [PMID: 28347910 PMCID: PMC5621379 DOI: 10.1016/j.bone.2017.03.047] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 03/23/2017] [Accepted: 03/23/2017] [Indexed: 12/11/2022]
Abstract
The lung interfaces with atmospheric oxygen via a large surface area and is perfused by the entire venous return bearing waste products collected from the whole body. It is logical that the lung is endowed with generous anti-oxidative capacity derived both locally and from the circulation. The single-pass pleiotropic alpha-Klotho (αKlotho) protein was discovered when its genetic disruption led to premature multi-organ degeneration and early death. The extracellular domain of αKlotho is cleaved by secretases and released into circulation as endocrine soluble αKlotho protein, exerting wide-ranging cytoprotective effects including anti-oxidation on distant organs including the lung, which exhibits high sensitivity to circulating αKlotho insufficiency. Because circulating αKlotho is derived mainly from the kidney, acute kidney injury (AKI) leads to systemic αKlotho deficiency that in turn increases the risks of pulmonary complications, i.e., edema and inflammation, culminating in the acute respiratory distress syndrome. Exogenous αKlotho increases endogenous anti-oxidative capacity partly via activation of the Nrf2 pathway to protect lungs against injury caused by direct hyperoxia exposure or AKI. This article reviews the current knowledge of αKlotho antioxidation in the lung in the setting of AKI as a model of circulating αKlotho deficiency, an under-recognized condition that weakens innate cytoprotective defenses and contributes to the dysfunction in distant organs.
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Affiliation(s)
- Connie C W Hsia
- Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America.
| | - Priya Ravikumar
- Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America
| | - Jianfeng Ye
- Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America
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Brass EP, Wang H, Hiatt WR. Multiple skeletal muscle mitochondrial DNA deletions in patients with unilateral peripheral arterial disease. Vasc Med 2016. [DOI: 10.1177/1358836x0000500405] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Peripheral arterial disease (PAD) is associated with metabolic derangements and accumulation of the common 4977 bp mitochondrial DNA (mtDNA) deletion mutation. The current study was undertaken to test the hypothesis that PAD is associated with multiple mtDNA deletions. Gastrocnemius biopsies were obtained from nine patients with unilateral PAD. DNA extracted from the biopsies was analyzed for mtDNA deletions using a primer- shift PCR strategy. Multiple primers and strict, prospective criteria were used to identify deletions. PAD was associated with multiple mtDNA deletions (average of 8.2 distinct deletions in muscle from the hemodynamically affected limb). mtDNA injury was present in both the worse- and less-affected limbs of the unilateral PAD patients, and the estimated degree of mtDNA injury was strongly correlated in the two limbs on an intra-subject basis. The 4977 bp deletion was frequently identified, but was not always the deletion of highest frequency in individual samples. The estimated relative frequency of the 4977 bp deletion was correlated with the overall mtDNA injury in the biopsies. In summary, PAD is associated with mtDNA injury as reflected by multiple deletion mutations. As the mutations are not limited to the ischemic limb in unilateral patients, they are unlikely to contribute to the pathophysiology of claudication.
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Affiliation(s)
- Eric P Brass
- Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Hong Wang
- Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA
| | - William R Hiatt
- Section of Vascular Medicine, Division of Geriatrics, University of Colorado Health Sciences Center and the Colorado Prevention Center, Denver, CO, USA
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Shoar Z, Goldenthal MJ, De Luca F, Suarez E. Mitochondrial DNA content and function, childhood obesity, and insulin resistance. Endocr Res 2016; 41:49-56. [PMID: 26513277 DOI: 10.3109/07435800.2015.1068797] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES The objectives of our study were to compare the mitochondrial enzyme activity between obese and non-obese children and to assess the association between mitochondrial DNA content and function and markers of metabolic syndrome. METHODS Clinical and anthropometric data of obese and normal-weight children ages 2-18 years were collected. We collected buccal swabs for mitochondrial respiratory enzymes (complex I, IV, and Citrate Synthase). In obese children only, serum levels of metabolic parameters and mitochondrial DNA from mononuclear cells were quantitated. RESULTS We recruited 75 obese and 65 normal-weight children. There was no difference in respiratory complex enzyme activity levels between obese and normal-weight subjects. In obese subjects, mitochondrial to nuclear DNA (mt/nDNA) ratio was significantly correlated with BMI Z-score and BMI percentile (p < 0.05, and p < 0.01, respectively), and the strength of this correlation was proportionate to the degree of obesity. We did not find any association between mt/nDNA ratio and metabolic parameters. We observed a significant positive association between complex IV activity and fasting insulin level (p < 0.05). Finally, fasting insulin explained 45% of the variation in the complex IV activity level (p < 0.05). CONCLUSION Our findings indicate that mitochondrial DNA content is directly related to obesity, but not to the markers of metabolic syndrome/insulin resistance in children. Longitudinal studies involving larger samples are needed to confirm our findings and help elucidate the relationship between mitochondrial function, adiposity, and insulin resistance.
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Affiliation(s)
| | - Michael J Goldenthal
- b Section of Child Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine , Philadelphia , PA , USA
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Lanzetti M, Pires KMP, Santos JC, Ribeiro ML, Borges RM, da Silva AJR, Porto LC, Benjamim CF, Valenca SS. Ready-to-drink Matte® tea (diet and regular) increased life span and pulmonary health in aged mice. Food Res Int 2013. [DOI: 10.1016/j.foodres.2013.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Leukocyte mitochondrial DNA alteration in systemic lupus erythematosus and its relevance to the susceptibility to lupus nephritis. Int J Mol Sci 2012; 13:8853-8868. [PMID: 22942739 PMCID: PMC3430270 DOI: 10.3390/ijms13078853] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Revised: 06/28/2012] [Accepted: 07/09/2012] [Indexed: 11/28/2022] Open
Abstract
The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA were extracted from leukocytes of the peripheral venous blood. The D310 sequence variations and copy number of mtDNA, and mRNA expression levels of mtDNA-encoded genes in leukocytes were determined by quantitative real-time polymerase chain reaction (Q-PCR) and PCR-based direct sequencing, respectively. We found that leukocyte mtDNA in SLE patients exhibited higher frequency of D310 heteroplasmy (69.4% vs. 48.9%, p = 0.022) and more D310 variants (2.2 vs. 1.7, p = 0.014) than those found in controls. Among normal controls and patients with low, medium or high SLE disease activity index (SLEDAI), an ever-increasing frequency of D310 heteroplasmy was observed (p = 0.021). Leukocyte mtDNA copy number tended to be low in patients of high SLEDAI group (p = 0.068), especially in those harboring mtDNA with D310 heteroplasmy (p = 0.020). Moreover, the mtDNA copy number was positively correlated with the mRNA level of mtDNA-encoded ND1 (NADH dehydrogenase subunit 1) (p = 0.041) and ATPase 6 (ATP synthase subunit 6) (p = 0.030) genes. Patients with more D310 variants were more susceptible to lupus nephritis (p = 0.035). Taken together, our findings suggest that decrease in the mtDNA copy number and increase in D310 heteroplasmy of mtDNA are related to the development and progression of SLE, and that the patients harboring more D310 variants of mtDNA are more susceptible to lupus nephritis.
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15
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Kumar PRV, Cheriyan VD, Seshadri M. Evaluation of Spontaneous DNA Damage in Lymphocytes of Healthy Adult Individuals from High-Level Natural Radiation Areas of Kerala in India. Radiat Res 2012; 177:643-50. [DOI: 10.1667/rr2681.1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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16
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Lee HC, Wei YH. Mitochondria and Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 942:311-27. [DOI: 10.1007/978-94-007-2869-1_14] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Lee HC, Chang CM, Chi CW. Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 2010; 9 Suppl 1:S47-58. [PMID: 20816876 DOI: 10.1016/j.arr.2010.08.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mitochondria are intracellular organelles responsible for generating ATP through respiration and oxidative phosphorylation (OXPHOS), producing reactive oxygen species, and initiating and executing apoptosis. Mitochondrial dysfunction has been observed to be an important hallmark of aging and cancer. Because mitochondrial DNA (mtDNA) is important in maintaining functionally competent organelles, accumulation of mtDNA mutations can affect energy production, oxidative stress, and cell survival, which may contribute to aging and/or carcinogenesis. This review outlines a variety of somatic mtDNA mutations identified in aging tissues and human cancers, as well as recent advances in understanding the causal role of mtDNA mutations in the aging process and cancer progression. Mitochondrial dysfunction elicited by somatic mutations in mtDNA could induce apoptosis in aging cells and some cancer cells with severe mtDNA mutations. In addition, it could activate mitochondria-to-nucleus retrograde signaling to modulate the expression of nuclear genes involved in a metabolic shift from OXPHOS to glycolysis, facilitate cells to adapt to altered environments and develop resistance to chemotherapeutic agents, or promote metastatic properties of cancer cells. These findings suggest that accumulation of somatic mtDNA mutations is not only an important contributor to human aging but also plays a critical role in cancer progression.
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Role of reactive oxygen species-elicited apoptosis in the pathophysiology of mitochondrial and neurodegenerative diseases associated with mitochondrial DNA mutations. J Formos Med Assoc 2009; 108:599-611. [PMID: 19666347 DOI: 10.1016/s0929-6646(09)60380-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
A wide spectrum of pathogenic mutations of mitochondrial DNA (mtDNA) has been demonstrated to cause mitochondrial dysfunction and overproduction of reactive oxygen species (ROS), in relation to mitochondrial and neurodegenerative diseases. Our previous studies have shown that large-scale deletions of mtDNA not only serve as an indicator of oxidative damage, but also result in greater susceptibility of human cells to apoptosis triggered by UV irradiation and other apoptotic stimuli. In this review, we focus on the involvement of mtDNA-mutation-associated oxidative stress and susceptibility to apoptosis in the pathophysiology of mitochondrial and neurodegenerative diseases. Different lines of research have provided concordant data to suggest that the mtDNA-mutation-elicited energy insufficiency and enhanced oxidative stress and damage lead to cell dysfunction, and increase the susceptibility of affected cells to apoptosis in patients with these diseases. Moreover, accumulating experimental evidence has shown that antioxidant therapy is a good strategy for decreasing intracellular ROS and alleviating oxidative-stress-induced apoptosis in cells of patients that harbor pathogenic mtDNA mutations.
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de Assis KRC, Ladeira MSP, Bueno RC, dos Santos BF, Dalben I, Salvadori DMF. Genotoxicity of cigarette smoking in maternal and newborn lymphocytes. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2009; 679:72-8. [DOI: 10.1016/j.mrgentox.2009.02.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2008] [Revised: 01/27/2009] [Accepted: 02/04/2009] [Indexed: 10/21/2022]
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Increased salivary level of 8-hydroxydeoxyguanosine is a marker of premature oxidative mitochondrial DNA damage in gingival tissue of patients with periodontitis. Arch Immunol Ther Exp (Warsz) 2009; 57:205-11. [DOI: 10.1007/s00005-009-0026-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2008] [Accepted: 01/28/2009] [Indexed: 10/20/2022]
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Song L, Zheng J, Li H, Jia N, Suo Z, Cai Q, Bai Z, Cheng D, Zhu Z. Prenatal Stress Causes Oxidative Damage to Mitochondrial DNA in Hippocampus of Offspring Rats. Neurochem Res 2008; 34:739-45. [DOI: 10.1007/s11064-008-9838-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 08/18/2008] [Indexed: 11/27/2022]
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Kawahara H, Fukura M, Tsuchishima M, Takase S. Mutation of mitochondrial DNA in livers from patients with alcoholic hepatitis and nonalcoholic steatohepatitis. Alcohol Clin Exp Res 2008; 31:S54-60. [PMID: 17331167 DOI: 10.1111/j.1530-0277.2006.00287.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND In alcoholic hepatitis (Al-Hep) and nonalcoholic steatohepatitis (NASH), triglycerides accumulate in hepatocytes. We examined the hypothesis that mutations in mitochondrial DNA may take place by mitochondrial overwork, resulting in dysfunction of mitochondria. SUBJECTS AND METHODS Subjects of this research were 8 cases each of Al-Hep, NASH, and fatty liver (FL). Total DNA was extracted from the biopsied liver samples. DNA fragments were amplified by PCR and DNA sequences determined in the control and coding regions of mitochondrion. RESULTS When the numbers of mutations per 1,000 bases of mitochondrial DNA were compared between each group, no significant differences were found among D-loop, HV1, and HV2 mitochondrial DNA regions. However, there were significantly more mutations in ND1 and COII of Al-Hep and NASH than in FL, and mutations were comparatively at random. Neither a region in which mutations were focused nor differences among the groups were recognized. When details of the base mutation in a control region were investigated by group, the transition type of mutation between T:A<<->>C:G occurred in at least 70%. Also, a transition-type mutation was found mostly in a coding region, which was similar to the mutation pattern in the control region, except for the ND1 and COII regions where there were hardly any mutations. CONCLUSIONS As gene mutations of mitochondrial DNA appeared frequently in Al-Hep, and also in NASH, mitochondrial dysfunction caused by mutation in mitochondrial DNA may be involved in the pathogenesis of both diseases.
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Affiliation(s)
- Hiromu Kawahara
- Department of Gastroenterology, Kanazawa Medical University, Ishikawa, Japan.
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24
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Chia T, Hsu CY, Chen HL. Oxidative damage of workers in secondary metal recovery plants affected by smoking status and joining the smelting work. INDUSTRIAL HEALTH 2008; 46:174-182. [PMID: 18413971 DOI: 10.2486/indhealth.46.174] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
In Taiwan, secondary copper smelters and zinc recovery plants primarily utilize recovering metal from scrap and dross, and handles mostly fly ash and slag with high temperature to produce ZnO from the iron and steel industry. The materials may contain organic impurities, such as plastic and organic chloride chemicals, and amounts of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) are produced during the smelting process. Therefore, secondary metal recovery industries are major emission sources of PCDD/Fs, which may have been demonstrated to elicit oxidative stress and to involve the production of plasma malondialdehyde (MDA). Many studies have also indicated that the intake of antioxidants, smoking, age and exposure to environmental pollutants may be implicated to DNA damage or lipid peroxidation. This study therefore aims to elucidate the roles of occupational exposure like joining the smelting work, age, smoking and alcohol status, and antioxidant intake on oxidative damage in secondary metal recovery workers in Taiwan. 73 workers were recruited from 2 secondary metal recovery plants. The analysis of 8-hydroxydeoxyguanosine (8-OH-dG) in urine, DNA strand breakage (comet assay) and lipid peroxidation (MDA) in blood samples were completed for all of the workers. The results showed that the older subjects exhibited significantly lower levels of 8-OH-dG and MDA than younger subjects. Our investigation also showed that working departments were in related to plasma MDA and DNA strand breakage levels of nonsmokers, however, the observation become negligible in smokers. And it is implicated that cigarette type might affect 8-OH-dG levels in secondary metal recovery workers. Since, adding to results above, the MDA level in production workers was significantly higher than those in managerial departments, it is important for the employers to make efforts on improving occupational environments or serving protective equipments to protect workers in secondary metal recovery factories.
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Affiliation(s)
- Taipau Chia
- Institute of Occupational Safety and Hazard Prevention, Hung Kuang University, Taiwan, ROC
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Tan D, Goerlitz DS, Dumitrescu RG, Han D, Seillier-Moiseiwitsch F, Spernak SM, Orden RA, Chen J, Goldman R, Shields PG. Associations between cigarette smoking and mitochondrial DNA abnormalities in buccal cells. Carcinogenesis 2008; 29:1170-7. [PMID: 18281252 PMCID: PMC2443276 DOI: 10.1093/carcin/bgn034] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
DNA alterations in mitochondria are believed to play a role in carcinogenesis and are found in smoking-related cancers. We sought to replicate earlier findings for the association of smoking with increased mitochondrial DNA (mtDNA) content in buccal cells and further hypothesized that there would be an increased number of somatic mtDNA mutations in smokers. Buccal cells and blood lymphocytes were studied from 42 healthy smokers and 30 non-smokers. Temporal temperature gradient electrophoresis screening and sequencing was used to identify mtDNA mutations. The relative mtDNA content was determined by real-time polymerase chain reaction. Assuming that mtDNA in lymphocytes represents the inherited sequence, it was found that 31% of smokers harbored at least one somatic mtDNA mutation in buccal cells with a total of 39 point mutations and 8 short deletions/insertions. In contrast, only 23% of non-smokers possessed mutations with a total of 10 point mutations and no insertions/deletions detected. mtDNA somatic mutation density was higher in smokers (0.68/10 000 bp per person) than in non-smokers (0.2/10 000 bp per person). There was a statistically significant difference in the pattern of homoplasmy and heteroplasmy mutation changes between smokers and non-smokers. Whereas non-smokers had the most mutations in D-loop region (70%), smokers had mutations in both messenger RNA encoding gene (36%) and D-loop region (49%). The mean ratio of buccal cells to lymphocytes of mtDNA content in smokers was increased (2.81) when compared with non-smokers (0.46). These results indicate that cigarette smoke exposure affects mtDNA in buccal cells of smokers. Additional studies are needed to determine if mitochondrial mutation assays provide new or complementary information for estimating cigarette smoke exposure at the cellular level or as a cancer risk biomarker.
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Affiliation(s)
- Duanjun Tan
- Cancer Genetics and Epidemiology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
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Leuner K, Hauptmann S, Abdel-Kader R, Scherping I, Keil U, Strosznajder JB, Eckert A, Müller WE. Mitochondrial dysfunction: the first domino in brain aging and Alzheimer's disease? Antioxid Redox Signal 2007; 9:1659-75. [PMID: 17867931 DOI: 10.1089/ars.2007.1763] [Citation(s) in RCA: 146] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
With the increasing average life span of humans and with decreasing cognitive function in elderly individuals, age-related cognitive disorders including dementia have become a major health problem in society. Aging-related mitochondrial dysfunction underlies many common neurodegenerative disorders diseases, including Alzheimer's disease (AD). AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein. In this review, the authors focus on the latest findings in AD animal models indicating that these histopathological alterations induce deficits in the function of the complexes of the respiratory chain and therefore consecutively result in mitochondrial dysfunction. This parameter is intrinsically tied to oxidative stress. Both are early events in aging and especially in the pathogenesis of aging-related severe neurodegeneration. Ginkgo biloba extract seems to be of therapeutic benefit in the treatment of mild to moderate dementia of different etiology, although the data are quite heterogeneous. Herein, the authors suggest that mitochondrial protection and subsequent reduction of oxidative stress are important components of the neuroprotective activity of Ginkgo biloba extract.
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Affiliation(s)
- Kristina Leuner
- Department of Pharmacology, Zafes, Biocenter, University of Frankfurt, Germany.
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Canakçi CF, Tatar A, Canakçi V, Cicek Y, Oztas S, Orbak R. New Evidence of Premature Oxidative DNA Damage: Mitochondrial DNA Deletion in Gingival Tissue of Patients With Periodontitis. J Periodontol 2006; 77:1894-900. [PMID: 17076616 DOI: 10.1902/jop.2006.060108] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Overproduction of reactive oxygen species (ROS) causes increased oxidative stress in gingival tissue. It has been generally accepted that increased oxidative stress might contribute to additional damage of lipids, proteins, and DNA molecules. The mitochondrial DNA (mtDNA) mutation is a superb biomarker of oxidative damage. The aim of the present study was to investigate the mtDNA deletions in the gingival tissue of patients with periodontitis and to explain the correlations between mtDNA deletion in gingival tissue and clinical parameters of periodontitis and age. METHODS Gingival tissue and blood samples were collected from 30 patients with chronic periodontitis (CP group) and 30 healthy control subjects (H group). To determine the clinical condition of each subject, the plaque index, gingival index, clinical attachment level, and probing depth were measured. Using the polymerase chain reaction (PCR) method, we examined the 7.4- and 5-kbp mtDNA deletions in tissue and blood samples. Three different pairs of PCR primers were used in this study. RESULTS In this study, we did not detect any deletions in blood DNA samples in either the CP or H group. Also, the 7.4-kbp mtDNA deletion was not detected in gingival tissues of subjects. However, the 5-kbp mtDNA deletion was detected in 24 of the 30 subjects (80%) in the CP group and was not detected in the H group (0%). Significant correlations were found between the occurrence of the 5-kbp mtDNA deletion and all clinical parameters (P <0.01). A similar correlation was found between the occurrence of the 5-kbp mtDNA deletion and age (P <0.05). CONCLUSIONS The overproduction of ROS by activated polymorphonuclear leukocytes in chronic inflammation may lead to premature oxidative damage of the mtDNA. In this study, the occurrence of the 5-kbp mtDNA deletion in 24 periodontitis subjects may be evidence of premature oxidative DNA damage.
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Affiliation(s)
- Cenk Fatih Canakçi
- Department of Periodontology, Faculty of Dentistry, Ataturk University, Erzurum, Turkey.
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Abstract
Mitochondria have long been known to play a critical role in maintaining the bioenergetic status of cells under physiological conditions. It was also recognized early in mitochondrial research that the reduction of oxygen to generate the free radical superoxide occurs at various sites in the respiratory chain and was postulated that this could lead to mitochondrial dysfunction in a variety of disease states. Over recent years, this view has broadened substantially with the discovery that reactive oxygen, nitrogen, and lipid species can also modulate physiological cell function through a process known as redox cell signaling. These redox active second messengers are formed through regulated enzymatic pathways, including those in the mitochondrion, and result in the posttranslational modification of mitochondrial proteins and DNA. In some cases, the signaling pathways lead to cytotoxicity. Under physiological conditions, the same mediators at low concentrations activate the cytoprotective signaling pathways that increase cellular antioxidants. Thus, it is critical to understand the mechanisms by which these pathways are distinguished to develop strategies that will lead to the prevention of cardiovascular disease. In this review, we describe recent evidence that supports the hypothesis that mitochondria have an important role in cell signaling, and so contribute to both the adaptation to oxidative stress and the development of vascular diseases.
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Affiliation(s)
- Jessica Gutierrez
- Department of Physiology and Biophysics, Center for Free Radical Biology, University of Alabama at Birmingham, USA
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Kregel KC, Zhang HJ. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 2006; 292:R18-36. [PMID: 16917020 DOI: 10.1152/ajpregu.00327.2006] [Citation(s) in RCA: 538] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Aging is an inherently complex process that is manifested within an organism at genetic, molecular, cellular, organ, and system levels. Although the fundamental mechanisms are still poorly understood, a growing body of evidence points toward reactive oxygen species (ROS) as one of the primary determinants of aging. The "oxidative stress theory" holds that a progressive and irreversible accumulation of oxidative damage caused by ROS impacts on critical aspects of the aging process and contributes to impaired physiological function, increased incidence of disease, and a reduction in life span. While compelling correlative data have been generated to support the oxidative stress theory, a direct cause-and-effect relationship between the accumulation of oxidatively mediated damage and aging has not been strongly established. The goal of this minireview is to broadly describe mechanisms of in vivo ROS generation, examine the potential impact of ROS and oxidative damage on cellular function, and evaluate how these responses change with aging in physiologically relevant situations. In addition, the mounting genetic evidence that links oxidative stress to aging is discussed, as well as the potential challenges and benefits associated with the development of anti-aging interventions and therapies.
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Affiliation(s)
- Kevin C Kregel
- Department of Integrative Physiology and Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA.
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Westerhoff LM, Merz KM. Quantum mechanical description of the interactions between DNA and water. J Mol Graph Model 2006; 24:440-55. [PMID: 16199192 DOI: 10.1016/j.jmgm.2005.08.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Revised: 08/24/2005] [Accepted: 08/26/2005] [Indexed: 11/25/2022]
Abstract
In recent years, a lot of attention has been focused on the electronic properties of DNA. With recent advances in linear scaling quantum mechanics there are now new tools available to enhance our understanding of the electronic properties of DNA among other biomolecules. Using both explicit solvent models and implicit (continuum) solvent models, the electronic characteristics of a dodecamer duplex DNA have been fully studied using both divide and conquer (D&C), semi-empirical quantum mechanics and non-D&C semi-empirical quantum mechanics. According to the AM1 Hamiltonian, approximately 3.5 electrons (approximately 0.3 electron/base pair) are transferred from the duplex to the solvent. According to the density of state (DOS) analysis, in vacuo DNA has a band gap of approximately 1 eV showing that in the absence of solvent, the DNA may exhibit similar properties to those of a semiconductor. Upon increasing solvation (2.5-5.5 A), the band gap ranges from approximately 3 eV to approximately 6 eV. For the implicit solvent model, the band gap continues this widening trend to approximately 7 eV. Therefore, upon solvation and in the absence of dopants, the DNA should begin to loose its conductive properties. Finally, when one considers the energy and localization of the frontier orbitals (HOMO and LUMO), solvent has a stabilizing effect on the DNA system. The energy of the HOMO drops from approximately 15 eV in vacuo to approximately 2 eV for 5.5 A of water to approximately -8 eV for the implicit solvent model. Similarly, the LUMO drops from approximately 16 eV for in vacuo to approximately 9 eV for 5.5 A of water to approximately -1 eV for the implicit model. Beyond the importance of the computed results on the materials properties of DNA, the present work also shows that the behavior of intercalators will be affected by the electronic properties of DNA. This could have an impact on our understanding of how DNA based drugs interact with DNA and on the design of new DNA based small molecule drugs.
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Affiliation(s)
- Lance M Westerhoff
- Department of Chemistry, 104 Chemistry Building, The Pennsylvania State University, University Park, PA 16802, USA
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Masayesva BG, Mambo E, Taylor RJ, Goloubeva OG, Zhou S, Cohen Y, Minhas K, Koch W, Sciubba J, Alberg AJ, Sidransky D, Califano J. Mitochondrial DNA content increase in response to cigarette smoking. Cancer Epidemiol Biomarkers Prev 2006; 15:19-24. [PMID: 16434581 DOI: 10.1158/1055-9965.epi-05-0210] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
An increase in mitochondrial DNA (mtDNA) content and decline in mitochondrial function occurs with aging and in response to DNA-damaging agents, including tobacco smoke. We did a cross-sectional study and quantified changes in mtDNA content in a population of individuals with varied smoking and alcohol exposure. Age, smoking history, ethanol intake, and other demographic data were characterized for 604 individuals participating in a screening study for smoking-related upper aerodigestive malignancy. Total DNA was extracted from exfoliated cells in saliva. DNA from a nuclear gene, beta-actin, and two mitochondrial genes, cytochrome c oxidase I and II (Cox I and Cox II), were quantified by real-time PCR. mtDNA content was correlated with age, exposure history, and other variables using multivariate regression analyses. A significant increase (P<0.001) in mtDNA content was noted in smokers (31% and 29% increase for Cox I and Cox II, respectively) and former smokers (31% and 34%) when compared with never smokers. This association persisted after adjustment for other significant factors including age, alcohol drinking, and income (P<0.001). Increased mtDNA content was positively associated with pack-years of smoking (P=0.02). Despite an average smoking cessation interval of 21 years in former smokers, tobacco cessation interval was not statistically significantly associated with mtDNA content. Smoking is associated with increased mtDNA content in a dose-dependent fashion. Mitochondrial DNA alterations in response to smoking persist for several decades after smoking cessation, consistent with long-term, smoking-related damage.
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Affiliation(s)
- Brett G Masayesva
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287-0910, USA
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Abstract
OBJECTIVE We sought to understand the pathophysiological effects of depression by examining group differences in serum levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative damage. METHODS Our sample consisted of 169 participants. Eight-four of these participants met diagnostic criteria for clinical depression. The 85 participants in our comparison group were matched on age, gender, and ethnicity to the depressed group. 8-OHdG was measured by enzyme-linked immunosorbent assay. RESULTS After adjusting for age, gender, race/ethnicity, years of education, daily smoking, average number of alcoholic drinks per week, average amount of physical activity per week, and body mass index, participants in the depressed group had significantly higher levels of oxidative DNA damage compared with participants in the control group. Pairwise comparisons showed that participants with major depression had significantly higher levels of 8-OHdG than control subjects and marginally higher levels of 8-OHdG compared with those with minor depression. Furthermore, participants with recurrent episodes of depression had more oxidative damage than participants with single episodes, who in turn had more damage than healthy control subjects. Finally, participants with recurrent episodes of major depression had more DNA damage than other depressed participants, who in turn had more damage than healthy control subjects. CONCLUSIONS Our findings suggest that increased oxidative damage may represent a common pathophysiological mechanism, whereby depressed individuals become vulnerable to comorbid medical illness.
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Affiliation(s)
- Michael J Forlenza
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
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Kim MM, Clinger JD, Masayesva BG, Ha PK, Zahurak ML, Westra WH, Califano JA. Mitochondrial DNA quantity increases with histopathologic grade in premalignant and malignant head and neck lesions. Clin Cancer Res 2005; 10:8512-5. [PMID: 15623632 DOI: 10.1158/1078-0432.ccr-04-0734] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Mitochondria are highly susceptible to oxidative damage. Although mitochondrial function decreases with oxidative damage, overall mitochondrial DNA (mtDNA) content increases to compensate for general mitochondrial dysfunction. We performed quantitative polymerase chain reaction for genes specific to mitochondrial and nuclear genomes to investigate relative mitochondrial abundance in a spectrum of dysplastic head and neck lesions. EXPERIMENTAL DESIGN DNA from mild, moderate, and severe dysplasias, as well as invasive tumors and normal mucosal cells, was extracted. Using quantitative polymerase chain reaction, mitochondrial to nuclear DNA ratios were determined by quantification of cytochrome c oxidase subunit 1 (CoxI) and beta-actin genes. RESULTS Mean CoxI/beta-actin DNA ratios for mild, moderate, and severe premalignant lesions were 0.0529, 0.0607, and 0.1021, respectively. The mean ratio for the normal mucosal cells contained in saliva was 0.0537, whereas the mean ratio for tumors was 0.1667. As a whole, our experimental model demonstrated significance (P = 0.0358). Comparisons between individual categories showed borderline significance when compared with the normal group, with P values of 0.0673, 0.0747, and 0.0824 for moderate and severe dysplasia and invasive tumor, respectively. CONCLUSIONS Head and neck squamous cell carcinomas arise through premalignant intermediates and may be merely morphologic manifestations of accumulated genetic alterations. In keeping with this molecular tumor progression model, our study shows that mtDNA increases according to histopathologic grade, a phenomenon that may be a feedback mechanism that compensates for a generalized decline in respiratory chain function. Therefore, high mtDNA content may be another marker of genetic alteration, a measure of relative DNA injury, and a surrogate measure of histopathologic grade.
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Affiliation(s)
- Michael M Kim
- Head and Neck Cancer Research Division, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-0910, USA
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Jiang WW, Masayesva B, Zahurak M, Carvalho AL, Rosenbaum E, Mambo E, Zhou S, Minhas K, Benoit N, Westra WH, Alberg A, Sidransky D, Koch W, Califano J. Increased mitochondrial DNA content in saliva associated with head and neck cancer. Clin Cancer Res 2005; 11:2486-91. [PMID: 15814624 DOI: 10.1158/1078-0432.ccr-04-2147] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Alterations of the mitochondrial DNA (mtDNA) have been described in human tumors and in other tissues in association with smoking exposure. We did quantitative PCR of cytochrome c oxidase I (Cox I) and cytochrome c oxidase II (Cox II) genes on oral rinse samples obtained from 94 patients with primary head and neck squamous cell carcinoma (HNSC) and a control group of 656 subjects. Mitochondrial DNA/nuclear DNA in saliva from HNSC patients and controls in relationship to smoking exposure, ethanol intake, and tumor stage were examined. Mean levels of Cox I and Cox II in saliva samples were significantly higher in HNSC patients: Cox I, 0.076 [95% confidence interval (95% CI), 0.06-0.09] and Cox II, 0.055 (95% CI, 0.04-0.07) in comparison with controls Cox I, 0.054 (95% CI, 0.05-0.06), P < 0.0001 and Cox II, 0.046 (95% CI, 0.04-0.05), P = 0.003 (t test). MtDNA levels were elevated in primary tumors when compared with matched, pretreatment saliva and significant correlation was noted (Cox I, r = 0.30, P = 0.005 and Cox II r = 0.33, P = 0.002, respectively, Pearson's correlation). On univariate analysis, smoking, age, HNSC diagnosis, and advanced stage of HNSC were associated with higher level of mtDNA content in saliva. Multivariate analysis showed a significant and independent association of HNSC diagnosis, age, and smoking with increasing mtDNA/nuclear DNA for Cox I and Cox II. mtDNA content alteration is associated with HNSC independently of age and smoking exposure, can be detected in saliva, and may be due to elevation in mtDNA content in primary HNSC.
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Affiliation(s)
- Wei-Wen Jiang
- Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Division, Baltimore, MD 21287-0910, USA
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Dai JG, Lei X, Min JX, Zhang GQ, Wei H. Mitochondrial DNA sequence analysis of two mouse hepatocarcinoma cell lines. World J Gastroenterol 2005; 11:264-7. [PMID: 15633228 PMCID: PMC4205414 DOI: 10.3748/wjg.v11.i2.264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study genetic difference of mitochondrial DNA (mtDNA) between two hepatocarcinoma cell lines (Hca-F and Hca-P) with diverse metastatic characteristics and the relationship between mtDNA changes in cancer cells and their oncogenic phenotype.
METHODS: Mitochondrial DNA D-loop, tRNAMet+Glu+Ile and ND3 gene fragments from the hepatocarcinoma cell lines with 1100, 1126 and 534 bp in length respectively were analysed by PCR amplification and restriction fragment length polymorphism techniques. The D-loop 3’ end sequence of the hepatocarcinoma cell lines was determined by sequencing.
RESULTS: No amplification fragment length polymorphism and restriction fragment length polymorphism were observed in tRNAMet+Glu+Ile, ND3 and D-loop of mitochondrial DNA of the hepatocarcinoma cells. Sequence differences between Hca-F and Hca-P were found in mtDNA D-loop.
CONCLUSION: Deletion mutations of mitochondrial DNA restriction fragment may not play a significant role in carcinogenesis. Genetic difference of mtDNA D-loop between Hca-F and Hca-P, which may reflect the environmental and genetic influences during tumor progression, could be linked to their tumorigenic phenotypes.
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MESH Headings
- Animals
- Base Sequence
- Carcinoma, Hepatocellular/genetics
- Cell Line, Tumor
- DNA Primers
- DNA, Mitochondrial/genetics
- Liver Neoplasms/genetics
- Mice
- Mutation
- Polymerase Chain Reaction
- Polymorphism, Restriction Fragment Length
- RNA, Transfer, Glu/genetics
- RNA, Transfer, Ile/genetics
- RNA, Transfer, Met/genetics
- Restriction Mapping
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Affiliation(s)
- Ji-Gang Dai
- Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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36
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Chen HJC, Chiu WL. Detection and quantification of 1,N6-ethenoadenine in human urine by stable isotope dilution capillary gas chromatography/negative ion chemical ionization/mass spectrometry. Chem Res Toxicol 2003; 16:1099-106. [PMID: 12971797 DOI: 10.1021/tx034057l] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
1,N(6)-Ethenoadenine (epsilonAde) is a promutagenic lesion detected in tissue DNA; it has been shown that epsilonAde can be repaired by human DNA glycosylases, and it is expected to be excreted in urine. In this paper, we present for the first time detection and accurate quantification of epsilonAde in human urine samples by a highly sensitive and specific stable isotope dilution gas chromatography/negative ion chemical ionization/mass spectrometric assay (GC/NICI/MS). Analysis by GC/NICI/MS includes adduct enrichment by a solid phase extraction column, followed by electrophore labeling and postderivatization cleanup. Using selective ion monitoring mode, the assay allows quantification of 0.5 pg of epsilonAde in as little as 0.1 mL of the urine sample, which is equivalent to corresponding concentration quantification limit of 31 pM. Using this assay, concentrations of epsilonAde in the 24 h urine samples of 23 healthy individuals were determined, which ranged from 0 to 124 pg/mL. After we adjusted for creatinine, a statistically significant correlation was found between epsilonAde excretion and cigarette smoking in males (p = 0.03). Thus, this stable isotope dilution GC/NICI/MS assay offers a sensitive and accurate quantification of urinary epsilonAde as a potential biomarker for oxidative damage of DNA and repair.
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Affiliation(s)
- Hauh-Jyun Candy Chen
- Department of Chemistry and Biochemistry, National Chung Cheng University, 160 San-Hsing, Ming-Hsiung, Chia-Yi 62142, Taiwan.
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37
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Affiliation(s)
- Yau-Huei Wei
- Department of Biochemistry, Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China
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38
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Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood) 2002; 227:671-82. [PMID: 12324649 DOI: 10.1177/153537020222700901] [Citation(s) in RCA: 390] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Mitochondria do not only produce less ATP, but they also increase the production of reactive oxygen species (ROS) as by-products of aerobic metabolism in the aging tissues of the human and animals. It is now generally accepted that aging-associated respiratory function decline can result in enhanced production of ROS in mitochondria. Moreover, the activities of free radical-scavenging enzymes are altered in the aging process. The concurrent age-related changes of these two systems result in the elevation of oxidative stress in aging tissues. Within a certain concentration range, ROS may induce stress response of the cells by altering expression of respiratory genes to uphold the energy metabolism to rescue the cell. However, beyond the threshold, ROS may cause a wide spectrum of oxidative damage to various cellular components to result in cell death or elicit apoptosis by induction of mitochondrial membrane permeability transition and release of apoptogenic factors such as cytochrome c. Moreover, oxidative damage and large-scale deletion and duplication of mitochondrial DNA (mtDNA) have been found to increase with age in various tissues of the human. Mitochondria act like a biosensor of oxidative stress and they enable cell to undergo changes in aging and age-related diseases. On the other hand, it has recently been demonstrated that impairment in mitochondrial respiration and oxidative phosphorylation elicits an increase in oxidative stress and causes a host of mtDNA rearrangements and deletions. Here, we review work done in the past few years to support our view that oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA mutations and defective antioxidant enzymes in human aging.
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Affiliation(s)
- Yau-Huei Wei
- Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
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39
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Lewis PD, Fradley SR, Griffiths AP, Baxter PW, Parry JM. Mitochondrial DNA mutations in the parotid gland of cigarette smokers and non-smokers. Mutat Res 2002; 518:47-54. [PMID: 12063066 DOI: 10.1016/s1383-5718(02)00066-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
It has previously been demonstrated that mitochondrial DNA (mtDNA) mutations accumulate in the lung and increase in frequency with age. It has also been shown that the level of mtDNA mutations including deletions and base substitutions are elevated in lung tissue of smokers relative to non-smokers. We have previously shown that the 'common' 4977 bp mtDNA deletion is present in the parotid (salivary) gland of smokers and non-smokers and that there is a significant increase in the level of this deletion in Warthins tumour, an oncocytoma of the parotid gland. In this study we used semi-quantitative PCR to confirm the presence of 4977 bp mtDNA deletion in the parotid gland of non-smokers and smokers. Importantly, we show that the deletion accumulates with age regardless of smoking status and that there was no significant difference in the level of the 4977 bp deletion in parotid tissue of smokers and non-smokers. Using strand conformational polymorphism (SSCP) and direct sequencing we also found 5/23 smokers had parotid tissue specific base substitutions: either an A/T to G/C transition at A4767 or a G/C to A/T transition at G4853. These results are evidence of age related increase in the 4977 bp deletion and a higher level of mutations, probably due to oxidative damage, in the parotid gland of smokers.
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Affiliation(s)
- P D Lewis
- School of Biological Sciences, University of Wales Swansea, Swansea SA2 8PP, UK.
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40
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El-Zayadi AR, Selim O, Hamdy H, El-Tawil A, Moustafa H. Heavy cigarette smoking induces hypoxic polycythemia (erythrocytosis) and hyperuricemia in chronic hepatitis C patients with reversal of clinical symptoms and laboratory parameters with therapeutic phlebotomy. Am J Gastroenterol 2002; 97:1264-5. [PMID: 12014742 DOI: 10.1111/j.1572-0241.2002.05718.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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41
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Halliwell B. Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging 2002; 18:685-716. [PMID: 11599635 DOI: 10.2165/00002512-200118090-00004] [Citation(s) in RCA: 1023] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.
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Affiliation(s)
- B Halliwell
- Department of Biochemistry, Faculty of Medicine, National University of Singapore, Singapore.
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42
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Cherng SH, Huang KH, Yang SC, Wu TC, Yang JL, Lee H. Human 8-oxoguanine DNA glycosylase 1 mRNA expression as an oxidative stress exposure biomarker of cooking oil fumes. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2002; 65:265-278. [PMID: 11911490 DOI: 10.1080/15287390252800855] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Epidemiological studies have indicated that the exposure to carcinogenic components formed during the cooking of food might be associated with lung cancer risk of Chinese women. Previous studies have confirmed that cooking oil fumes from frying fish (COF) contained relatively high amount of benzo[a]pyrene, 2-methyl-3,8-dimethylimidazo[4,5-f] qunoxaline, benzene, and 1,3-butadiene, reported in fumes from heated soybean oil. Thus, we consider that oxidative stress induced by COF may play a role in lung cancer development among Chinese women. To verify whether the oxidative DNA damage was induced by COF, high-performance liquid chromatography (HPLC) analysis data showed that the levels of 8-hydroxydeoxyguanine (8-OH dG) were increased in a dose-dependent manner when calf thymus DNA reacted with various concentrations of COF. Since human 8-oxoguanine DNA glycosylase 1 (hOGG1) was a repair enzyme for removing 8- OH dG from damaged DNA, we hypothesized that hOGG1 mRNA may be used to assess the risk of oxidative damage induced by the exposure of COF. The results from reverse-transcription polymerase chain reaction showed that the hOGG1 mRNA expression was induced by hydrogen peroxide (H2O2) and COF in human lung adenocarcinoma CL-3 cells. To elucidate whether hOGG1 mRNA expression was an exposure biomarker of COF, a cross-sectional study of 238 subjects including 94 professional cooks, 43 housewives, and 101 COF-nonexposed control subjects was conducted. The hOGG1 mRNA expression frequencies of COF-exposed cooks (27 of 94, 28.7%) and housewives (6 of 43, 14%) were significantly higher than those of control subjects (4 of 101, 4%). After adjusting for age, sex, and smoking and drinking status, the odds risks (ORs) of housewives versus control and cooks versus control were 3.94 (95% confidence interval [CI] = 0.95-16.62) and 10.12 (95% CI = 2.83-36.15), respectively. These results indicated that hOGG1 may be adequate to act as an exposure biomarker to assess the oxidative DNA damage induced by COF. This also suggests that oxidative stress induced by COF may play a role in lung cancer development among Chinese women.
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Affiliation(s)
- Shur-Hueih Cherng
- Institute of Toxicology, Chung Shan Medical University, Taichung, Taiwan, Republic of China
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43
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Lee HC, Yin PH, Yu TN, Chang YD, Hsu WC, Kao SY, Chi CW, Liu TY, Wei YH. Accumulation of mitochondrial DNA deletions in human oral tissues -- effects of betel quid chewing and oral cancer. Mutat Res 2001; 493:67-74. [PMID: 11516716 DOI: 10.1016/s1383-5718(01)00160-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Accumulation of mitochondrial DNA (mtDNA) mutations in human tissues has been associated with intrinsic aging and environmental insult. Recently, mtDNA mutations have been detected in various tumors, including head and neck tumors. However, the factors affecting the occurrence and accumulation of mtDNA deletions in tumor tissues are poorly understood. In Taiwan, betel quid chewing is a major risk factor for oral cancer. Using polymerase chain reaction (PCR) techniques, we examined large-scale deletions of mtDNA in 53 pairs of tumor and non-tumor oral tissues from the patients with or without betel quid chewing history. The results revealed that irrespective of the history of betel quid chewing, the incidences of the 4977bp deletion and other deletions of mtDNA were lower in the tumor portion as compared with the non-tumor portion. The average proportions of the 4977bp deleted mtDNA in the tumor tissues of the betel quid chewers and non-betel quid chewers were 13- and 5-fold, respectively, lower than those in the corresponding non-tumor tissues. Moreover, the average proportion of 4977bp deleted mtDNA was significantly higher (P<0.05) in the non-tumor oral tissues of the patients with betel quid chewing history than that of the patients without the history of betel quid chewing. These results suggest that betel quid chewing may increase mtDNA mutation in human oral tissues and that accumulation of mtDNA deletions and subsequent cytoplasmic segregation of these mutations during cell division could be an important contributor to the early phase of oral carcinogenesis.
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Affiliation(s)
- H C Lee
- Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan, ROC
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44
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Wei YH, Lee CF, Lee HC, Ma YS, Wang CW, Lu CY, Pang CY. Increases of mitochondrial mass and mitochondrial genome in association with enhanced oxidative stress in human cells harboring 4,977 BP-deleted mitochondrial DNA. Ann N Y Acad Sci 2001; 928:97-112. [PMID: 11795533 DOI: 10.1111/j.1749-6632.2001.tb05640.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
In order to investigate the effect of aging- and disease-associated deletion of mtDNA on cellular functions, we used cytoplasm fusion to construct a series of the cybrids harboring varying proportions of mtDNA with 4,977 bp deletion from skin fibroblasts of a patient with chronic progressive external ophthalmoplegia. The cybrids were grown in the Dulbecco's modified Eagle medium supplemented with 5% fetal bovine serum, 100 microg/ml pyruvate and 50 microg/ml uridine. The population doubling time was longer for the cybrids containing higher proportions of 4,977 bp-deleted mtDNA. In addition, we found that the respiratory function was decreased with the increase of mtDNA with 4,977 bp deletion in the cybrids. Since impairment of the respiratory system of mitochondria increases the electron leak of the respiratory chain, we further determined the oxidative stress in these cybrids. The results showed that the specific contents of 8-hydroxy 2'-deoxyguanosine and lipid peroxides of the cybrids harboring > 65% of the 4,977 bp-deleted mtDNA were significantly increased as compared with those of the cybrids containing undetectable mutant mtDNA. On the other hand, we found that the mitochondrial mass and the relative content of the mitochondrial genome in the cybrids harboring 4,977 bp-deleted mtDNA were higher than those of the cybrids containing only wild type mtDNA. The relative content of mtDNA was increased 17% and 30%, respectively, in the cybrids harboring 17% and 56% of mtDNA with 4,977 bp deletion. Moreover, both mitochondrial mass and mtDNA content were concurrently increased by treatment of the cybrids with 180 microM of hydrogen peroxide. Taken these findings together, we conclude that increase of mitochondrial mass and mtDNA are the molecular events associated with enhanced oxidative stress in human cells with impaired respiratory function caused by mtDNA deletion.
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Affiliation(s)
- Y H Wei
- Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
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45
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Corradi M, Montuschi P, Donnelly LE, Pesci A, Kharitonov SA, Barnes PJ. Increased nitrosothiols in exhaled breath condensate in inflammatory airway diseases. Am J Respir Crit Care Med 2001; 163:854-8. [PMID: 11282756 DOI: 10.1164/ajrccm.163.4.2001108] [Citation(s) in RCA: 154] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Nitrosothiols (RS-NOs) are formed by interaction of nitric oxide (NO) with glutathione and may limit the detrimental effect of NO. Because NO generation is increased in airway inflammation, we have measured RS-NOs in exhaled breath condensate in patients with asthma, cystic fibrosis, or chronic obstructive pulmonary disease (COPD). We also measured exhaled NO and nitrite (NO(2-)) in the same subjects. RS-NOs were detectable in exhaled breath condensate of all subjects. RS-NOs were higher in subjects with severe asthma (0.81 +/- 0.06 microM) when compared with normal control subjects (0.11 +/- 0.02 microM, p < 0.01) and with subjects with mild asthma (0.08 +/- 0.01 microM, p < 0.01). Elevated RS-NOs values were also found in patients with cystic fibrosis (0.35 +/- 0.07 microM, p < 0.01), in those with COPD (0.24 +/- 0.04 microM, p < 0.01) and in smokers (0.46 +/- 0.09 microM, p < 0.01). In current smokers there was a correlation (r = 0.8, p < 0.05) between RS-NOs values and smoking history (pack/year). We also found elevated concentrations of NO(2-) in patients with severe asthma, cystic fibrosis, or COPD, but not in smokers or patients with mild asthma. This suggests that exhaled NO(2-) is less sensitive than exhaled RS-NOs. This study has shown that RS-NOs are detectable in exhaled breath condensate of healthy subjects and are increased in patients with inflammatory airway diseases. As RS-NOs concentrations in exhaled breath condensate vary in the different airway diseases and increase with the severity of asthma, their measurement may have clinical relevance as a noninvasive biomarker of nitrosative stress.
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Affiliation(s)
- M Corradi
- Institute of Respiratory Diseases, University of Parma, Italy
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46
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Lim PS, Cheng YM, Wei YH. Large-scale mitochondrial DNA deletions in skeletal muscle of patients with end-stage renal disease. Free Radic Biol Med 2000; 29:454-63. [PMID: 11020667 DOI: 10.1016/s0891-5849(00)00334-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
End-stage renal disease (ESRD) is associated with enhanced oxidative stress. This disease state provides a unique system for investigating the deleterious effect of exogenous sources of free radicals and reactive oxygen species (ROS) on mitochondrial DNA (mtDNA). To test the hypothesis that uremic milieu might cause more severe damage to mtDNA, we investigated the prevalence and abundance of mtDNA deletions in the skeletal muscles of ESRD patients. The results showed that the frequencies of occurrence of the 4977 bp and 7436 bp deletions of mtDNA in the muscle tissues of the older ESRD patients were higher than those of the younger patients. The frequency of occurrence of the 4977 bp-deleted mtDNA in the muscle was 33.3% for the patients in the age group of < 40 years, 66.6% in the 41-60-year-old group, 100% in the 61-80-year-old group, and 100% in patients >80 years of age, respectively. Only 22% of the normal aged controls carried the 4977 bp mtDNA deletion, whereas 77% (17/22) of the ESRD patients exhibited the mtDNA deletion. Using a semiquantitative PCR method, we determined the proportion of the 4977 bp-deleted mtDNA from the muscles that had been confirmed to harbor the deletion. We found that the proportions of the 4977 bp-deleted mtDNA in the muscle were significantly higher than those of the aged matched controls. Using long-range PCR techniques, a distinctive array of mtDNA deletions was demonstrated in the muscle of uremic patients. In summary, we found diverse and multiple mtDNA deletions in the skeletal muscles of ESRD patients. These deletions are more prevalent and abundant in ESRD patients than those found in normal populations. Accumulation of uremic toxins and impaired free radical scavenging systems may be responsible for the increased oxidative stress in ESRD patients. Such stress may result in oxidative damage and aging-associated mutation of the mitochondrial genome.
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Affiliation(s)
- P S Lim
- Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
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47
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Piyathilake CJ, Bell WC, Johanning GL, Cornwell PE, Heimburger DC, Grizzle WE. The accumulation of ascorbic acid by squamous cell carcinomas of the lung and larynx is associated with global methylation of DNA. Cancer 2000; 89:171-6. [PMID: 10897014 DOI: 10.1002/1097-0142(20000701)89:1<171::aid-cncr22>3.0.co;2-o] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Cigarette smokers are known to have lower concentrations of circulating ascorbic acid than nonsmokers. In contrast, there is evidence that the extracellular fluid lining of the alveolus, which comes in close contact with cigarette smoke, and the alveolar macrophages of smokers are enriched with ascorbic acid. The clinical significance of these observations is unknown. METHODS The authors measured the ascorbic acid concentrations and radiolabeled methyl incorporation (which is inversely related to the degree of DNA methylation in vivo) of paired samples of squamous cell carcinoma (SCC) and adjacent uninvolved mucosa of the lung and larynx (n = 22). RESULTS Cancerous tissues had significantly higher ascorbic acid concentrations (mean +/- standard deviation [SD, 485 +/- 77; median, 483 ng/mg protein) compared with their matched uninvolved tissues (mean +/- SD, 151 +/- 52; median, 72 ng/mg protein; P < 0.0001). The radiolabeled methyl incorporation was significantly higher in cancerous tissues (mean +/- SD, 31,419 +/- 2629; median, 31,416 counts per minute [CPM]/microg DNA) compared with their matched uninvolved tissues (mean +/- SD, 11,883 +/- 1567; median, 11,444 CPM/microg DNA; P < 0.0001). The Spearman correlation between ascorbic acid concentrations and radiolabeled methyl incorporation by DNA in SCCs was inverse and statistically significant (r = -0.58, P = 0.008), indicating a beneficial effect of accumulated ascorbic acid in global methylation of DNA. In the uninvolved tissues, this correlation was inverse but statistically not significant (r = -0.20, P =0.35). CONCLUSIONS Cancerous tissues of the lung and larynx demonstrated their ability to accumulate ascorbic acid. The accumulation of ascorbic acid by these tissues seemed to facilitate global methylation of DNA.
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Affiliation(s)
- C J Piyathilake
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
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48
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Legault J, Carrier C, Petrov P, Renard P, Remacle J, Mirault ME. Mitochondrial GPx1 decreases induced but not basal oxidative damage to mtDNA in T47D cells. Biochem Biophys Res Commun 2000; 272:416-22. [PMID: 10833429 DOI: 10.1006/bbrc.2000.2800] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The production of oxyradicals by mitochondria (mt) is a source of oxidative damage to mtDNA such as 8-oxo-dG lesions that may lead to mutations and mitochondrial dysfunction. The potential protection of mtDNA by glutathione peroxidase-1 (GPx1) was investigated in GPx1-proficient (GPx-2) and GPx1-deficient (Hygro-3) human breast T47D cell transfectants. GPx activity and GPx1-like antigen concentration in mitochondria were respectively at least 100-fold and 20- to 25-fold higher in GPx2 than Hygro-3 cells. In spite of this large difference in peroxide-scavenging capacity, the basal 8-oxo-dG frequency in mtDNA, assessed by carefully controlled postlabeling assay, was strikingly similar in both cell lines. In contrast, in response to menadione-mediated oxidative stress, induction of 8-oxo-dG and DNA strand breaks was much lower in the GPx1-proficient mitochondria (e.g., +14% 8-oxo-dG versus +54% in Hygro-3 after 1-h exposure to 25 microM menadione, P < 0.05). Our data indicate that the mitochondrial glutathione/GPx1 system protected mtDNA against damage induced by oxidative stress, but did not prevent basal oxidative damage to mtDNA, which, surprisingly, appeared independent of GPx1 status in the T47D model.
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Affiliation(s)
- J Legault
- Unit of Health and Environment, CHUL Research Center and Laval University, Québec, Canada
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49
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Lee HC, Yin PH, Lu CY, Chi CW, Wei YH. Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem J 2000. [PMID: 10816438 DOI: 10.1042/bj3480425] [Citation(s) in RCA: 280] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mitochondrial respiratory function is impaired in the target tissues of patients with mitochondrial diseases and declines with age in various human tissues. It is generally accepted that respiratory-chain defects result in enhanced production of reactive oxygen species and free radicals in mitochondria. Recently, we have demonstrated that the copy number of mitochondrial DNA (mtDNA) is increased in the lung tissues of elderly human subjects. The mtDNA copy number was suggested to be increased by a feedback mechanism that compensates for defects in mitochondria harbouring mutated mtDNA and a defective respiratory system. However, the detailed mechanism remains unclear. In this study, we treated a human lung fibroblast cell line, MRC-5, with H(2)O(2) at concentrations of 90-360 microM. After the treatment for 24-72 h, we found that cells were arrested at G(0) and G(1) phases but that mitochondrial mass and mtDNA content were significantly increased in a concentration- and time-dependent manner. Moreover, the oxidative stress induced by buthionine sulphoximine was also found to cause an increase in mitochondrial mass of the treated cells. Increased uptake of a vital mitochondrial dye Rhodamine 123 and enhanced tetrazolium [MTT, 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] reduction revealed that the mitochondria increased by H(2)O(2) treatment were functional. In addition, the increase in the mitochondrial mass was also observed in cell-cycle-arrested cells induced by mimosine, lovastatin and genistein. Taken together, these findings suggest that the increase in mitochondrial mass and mtDNA content are the early molecular events of human cells in response to endogenous or exogenous oxidative stress through cell-cycle arrest.
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Affiliation(s)
- H C Lee
- Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 112, Republic of China
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50
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Traber MG, van der Vliet A, Reznick AZ, Cross CE. Tobacco-related diseases. Is there a role for antioxidant micronutrient supplementation? Clin Chest Med 2000; 21:173-87, x. [PMID: 10763098 DOI: 10.1016/s0272-5231(05)70016-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
It is clear that smoking causes an increase in free radicals, reactive nitrogen and oxygen species (RNS and ROS, respectively), and that cigarette smoking is associated with increases in the incidence and severity of several diseases including atherosclerosis, cancer, and chronic obstructive lung disease. Although there is still no unequivocal evidence that oxidative stress is a contributor to these diseases or that an increased intake of antioxidant nutrients is beneficial, the observation that smokers have lower circulating levels of some of these nutrients, raises concern. This article discusses the possible links between the observed oxidant-induced damage related to tobacco smoking, effects on cellular mechanisms, and their potential involvement in the causation and enhancement of disease processes.
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Affiliation(s)
- M G Traber
- Linus Pauling Institute, Oregon State University, Corvallis, USA.
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