|
1
|
Giacco A, Petito G, Silvestri E, Scopigno N, Vigliotti M, Mercurio G, de Lange P, Lombardi A, Moreno M, Goglia F, Lanni A, Senese R, Cioffi F. Comparative effects of 3,5-diiodo-L-thyronine and 3,5,3'-triiodo-L-thyronine on mitochondrial damage and cGAS/STING-driven inflammation in liver of hypothyroid rats. Front Endocrinol (Lausanne) 2024; 15:1432819. [PMID: 39301315 PMCID: PMC11410700 DOI: 10.3389/fendo.2024.1432819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 08/07/2024] [Indexed: 09/22/2024] Open
Abstract
Maintaining a well-functioning mitochondrial network through the mitochondria quality control (MQC) mechanisms, including biogenesis, dynamics and mitophagy, is crucial for overall health. Mitochondrial dysfunction caused by oxidative stress and further exacerbated by impaired quality control can trigger inflammation through the release of the damage-associated molecular patterns (mtDAMPs). mtDAMPs act by stimulating the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway. Recently, aberrant signalling of the cGAS-STING axis has been recognised to be closely associated with several sterile inflammatory diseases (e.g. non-alcoholic fatty liver disease, obesity). This may fit the pathophysiology of hypothyroidism, an endocrine disorder characterised by the reduction of thyroid hormone production associated with impaired metabolic fluxes, oxidative balance and inflammatory status. Both 3,5,3'-triiodo-L-tyronine (T3) and its derivative 3,5-diiodo-L-thyronine (3,5-T2), are known to mitigate processes targeting mitochondria, albeit the underlying mechanisms are not yet fully understood. Therefore, we used a chemically induced hypothyroidism rat model to investigate the effect of 3,5-T2 or T3 administration on inflammation-related factors (inflammatory cytokines, hepatic cGAS-STING pathway), oxidative stress, antioxidant defence enzymes, mitochondrial DNA (mtDNA) damage, release and repair, and the MQC system in the liver. Hypothyroid rats showed: i) increased oxidative stress, ii) accumulation of mtDNA damage, iii) high levels of circulating cytokines, iv) hepatic activation of cGAS-STING pathways and v) impairment of MQC mechanisms and autophagy. Both iodothyronines restored oxidative balance by enhancing antioxidant defence, preventing mtDNA damage through the activation of mtDNA repair mechanisms (OGG1, APE1, and POLγ) and promoting autophagy progression. Concerning MQC, both iodothyronines stimulated mitophagy and dynamics, with 3,5-T2 activating fusion and T3 modulating both fusion and fission processes. Moreover, only T3 enhanced mitochondrial biogenesis. Notably, 3,5-T2, but not T3, reversed the hypothyroidism-induced activation of the cGAS-STING inflammatory cascade. In addition, it is noteworthy that 3,5-T2 seems more effective than T3 in reducing circulating pro-inflammatory cytokines IL-6 and IL-1B and in stimulating the release of IL-10, a known anti-inflammatory cytokine. These findings reveal novel molecular mechanisms of hepatic signalling pathways involved in hypothyroidism, which could be targeted by natural iodothyronines, particularly 3,5-T2, paving the way for the development of new treatment strategies for inflammatory diseases.
Collapse
Affiliation(s)
- Antonia Giacco
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| | - Giuseppe Petito
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Elena Silvestri
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| | - Nicla Scopigno
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| | - Michela Vigliotti
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| | - Giovanna Mercurio
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| | - Pieter de Lange
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Assunta Lombardi
- Department of Biology, University of Naples Federico II, Napoli, Italy
| | - Maria Moreno
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| | - Fernando Goglia
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| | - Antonia Lanni
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Rosalba Senese
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Federica Cioffi
- Department of Science and Technologies, University of Sannio, Benevento, Italy
| |
Collapse
|
|
2
|
Biswas S, Baruah M, Shil A, Sarkar S, Ali M, Samanta A, Bhuniya S. Polarity-Driven Two-Photon Fluorescent Probe for Monitoring the Perturbation in Lipid Droplet Levels during Mitochondrial Dysfunction and Acute Pancreatitis. ACS Sens 2023; 8:3793-3803. [PMID: 37815484 DOI: 10.1021/acssensors.3c01245] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
Lipid droplets (LDs) act as an energy reservoir in cancer cells; on the other hand, mitochondria are hyperactive to fulfill the energy demand to accelerate cell proliferation. We are interested in unfolding the relationship between the cellular energy reservoir and energy producer through fluorescence labeling. Thus, a dual organelle-targeted fluorescent probe MLD-1 has been rationally developed. It visualized the crosstalk between mitochondrial dysfunction and the fluctuation of LDs in live cells. Its two-photon ability allowed us to acquire deep tissue images. For the first time, we have shown that the probe has the ability to track the accumulation of LDs in different mouse organs during pancreatic inflammation. MLD-1, being a selectively polarity-driven, chemo- and photostable LD probe, may offer great possibilities for studying LD-associated biology in due course.
Collapse
Affiliation(s)
- Shayeri Biswas
- Centre for Interdisciplinary Sciences, JIS Institute of Advanced Studies and Research, JIS University, Arch Waterfront, GP Block, Sector V, Bidhannagar, Kolkata 700091, India
| | - Mousumi Baruah
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, Shiv Nadar Institution of Eminence, Delhi NCR, NH 91, Tehsil Dadri, Gautam Buddha Nagar, Uttar Pradesh 201314, India
| | - Anushree Shil
- Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk 37673, Republic of Korea
| | - Sourav Sarkar
- Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk 37673, Republic of Korea
| | - Mudassar Ali
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, Shiv Nadar Institution of Eminence, Delhi NCR, NH 91, Tehsil Dadri, Gautam Buddha Nagar, Uttar Pradesh 201314, India
| | - Animesh Samanta
- Molecular Sensors and Therapeutics Research Laboratory, Department of Chemistry, Shiv Nadar Institution of Eminence, Delhi NCR, NH 91, Tehsil Dadri, Gautam Buddha Nagar, Uttar Pradesh 201314, India
| | - Sankarprasad Bhuniya
- Centre for Interdisciplinary Sciences, JIS Institute of Advanced Studies and Research, JIS University, Arch Waterfront, GP Block, Sector V, Bidhannagar, Kolkata 700091, India
| |
Collapse
|
|
3
|
Guo L, Liu X, Su X. The role of TEMRA cell-mediated immune senescence in the development and treatment of HIV disease. Front Immunol 2023; 14:1284293. [PMID: 37901239 PMCID: PMC10602809 DOI: 10.3389/fimmu.2023.1284293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 09/29/2023] [Indexed: 10/31/2023] Open
Abstract
Human Immunodeficiency Virus (HIV) has plagued human society for a long time since its discovery, causing a large number of patients to suffer and costing hundreds of millions of medical services every year. Scientists have found that HIV and antiretroviral therapy accelerate immune aging by inducing mitochondrial dysfunction, and that terminal effector memory T cells (TEMRA cells) are crucial in immune aging. This specific subset of effector memory T cells has terminally differentiated properties and exhibits high cytotoxicity and proinflammatory capacity. We therefore explored and described the interplay between exhaustion features, essential markers, functions, and signaling pathways from previous studies on HIV, antiretroviral therapy, immune senescence, and TEMRA cells. Their remarkable antiviral capacity is then highlighted by elucidating phenotypic changes in TEMRA cells during HIV infection, describing changes in TEMRA cells before, during, and after antiretroviral therapy and other drug treatments. Their critical role in complications and cytomegalovirus (CMV)-HIV superinfection is highlighted. These studies demonstrate that TEMRA cells play a key role in the antiviral response and immune senescence during HIV infection. Finally, we review current therapeutic strategies targeting TEMRA cells that may be clinically beneficial, highlight their potential role in HIV-1 vaccine development, and provide perspectives and predictions for related future applications.
Collapse
Affiliation(s)
- Lihui Guo
- Department of Burns and Plastic Surgery, Yanbian University Hospital, Yanji, China
- Department of Rheumatology and Immunology, The First Hospital of China Medical University, China Medical University, Shen Yang, China
| | - Xudong Liu
- Department of Rheumatology and Immunology, The First Hospital of China Medical University, China Medical University, Shen Yang, China
| | - Xin Su
- Department of Burns and Plastic Surgery, Yanbian University Hospital, Yanji, China
| |
Collapse
|
|
4
|
Tang H, Zheng Z, Wang H, Wang L, Zhao G, Wang P. Vitamin K2 Modulates Mitochondrial Dysfunction Induced by 6-Hydroxydopamine in SH-SY5Y Cells via Mitochondrial Quality-Control Loop. Nutrients 2022; 14:1504. [PMID: 35406117 PMCID: PMC9003256 DOI: 10.3390/nu14071504] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 03/31/2022] [Accepted: 04/02/2022] [Indexed: 11/25/2022] Open
Abstract
Vitamin K2, a natural fat-soluble vitamin, is a potent neuroprotective molecule, owing to its antioxidant effect, but its mechanism has not been fully elucidated. Therefore, we stimulated SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) in a proper dose-dependent manner, followed by a treatment of vitamin K2. In the presence of 6-OHDA, cell viability was reduced, the mitochondrial membrane potential was decreased, and the accumulation of reactive oxygen species (ROS) was increased. Moreover, the treatment of 6-OHDA promoted mitochondria-mediated apoptosis and abnormal mitochondrial fission and fusion. However, vitamin K2 significantly suppressed 6-OHDA-induced changes. Vitamin K2 played a significant part in apoptosis by upregulating and downregulating Bcl-2 and Bax protein expressions, respectively, which inhibited mitochondrial depolarization, and ROS accumulation to maintain mitochondrial structure and functional stabilities. Additionally, vitamin K2 significantly inhibited the 6-OHDA-induced downregulation of the MFN1/2 level and upregulation of the DRP1 level, respectively, and this enabled cells to maintain the dynamic balance of mitochondrial fusion and fission. Furthermore, vitamin K2 treatments downregulated the expression level of p62 and upregulated the expression level of LC3A in 6-OHDA-treated cells via the PINK1/Parkin signaling pathway, thereby promoting mitophagy. Moreover, it induced mitochondrial biogenesis in 6-OHDA damaged cells by promoting the expression of PGC-1α, NRF1, and TFAM. These indicated that vitamin K2 can release mitochondrial damage, and that this effect is related to the participation of vitamin K2 in the regulation of the mitochondrial quality-control loop, through the maintenance of the mitochondrial quality-control system, and repair mitochondrial dysfunction, thereby alleviating neuronal cell death mediated by mitochondrial damage.
Collapse
Affiliation(s)
- Hengfang Tang
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (H.T.); (H.W.); (L.W.); (G.Z.)
- Science Island Branch of Graduate, University of Science and Technology of China, Hefei 230026, China
| | - Zhiming Zheng
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (H.T.); (H.W.); (L.W.); (G.Z.)
| | - Han Wang
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (H.T.); (H.W.); (L.W.); (G.Z.)
- Anhui Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Li Wang
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (H.T.); (H.W.); (L.W.); (G.Z.)
| | - Genhai Zhao
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; (H.T.); (H.W.); (L.W.); (G.Z.)
| | - Peng Wang
- Anhui Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
- CAS (Hefei) Institute of Technology Innovation Co., Ltd., Hefei 230088, China
| |
Collapse
|
|
5
|
Lushchak VI, Duszenko M, Gospodaryov DV, Garaschuk O. Oxidative Stress and Energy Metabolism in the Brain: Midlife as a Turning Point. Antioxidants (Basel) 2021; 10:1715. [PMID: 34829586 PMCID: PMC8614699 DOI: 10.3390/antiox10111715] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 01/10/2023] Open
Abstract
Neural tissue is one of the main oxygen consumers in the mammalian body, and a plentitude of metabolic as well as signaling processes within the brain is accompanied by the generation of reactive oxygen (ROS) and nitrogen (RNS) species. Besides the important signaling roles, both ROS and RNS can damage/modify the self-derived cellular components thus promoting neuroinflammation and oxidative stress. While previously, the latter processes were thought to progress linearly with age, newer data point to midlife as a critical turning point. Here, we describe (i) the main pathways leading to ROS/RNS generation within the brain, (ii) the main defense systems for their neutralization and (iii) summarize the recent literature about considerable changes in the energy/ROS homeostasis as well as activation state of the brain's immune system at midlife. Finally, we discuss the role of calorie restriction as a readily available and cost-efficient antiaging and antioxidant lifestyle intervention.
Collapse
Affiliation(s)
- Volodymyr I. Lushchak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., 76018 Ivano-Frankivsk, Ukraine; (V.I.L.); (D.V.G.)
- Department of Medical Biochemistry, I. Horbachevsky Ternopil National Medical University, 46002 Ternopil, Ukraine
- Research and Development University, 13a Shota Rustaveli Str., 76018 Ivano-Frankivsk, Ukraine
| | - Michael Duszenko
- Department of Neurophysiology, Institute of Physiology, University of Tübingen, 72074 Tübingen, Germany;
| | - Dmytro V. Gospodaryov
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., 76018 Ivano-Frankivsk, Ukraine; (V.I.L.); (D.V.G.)
| | - Olga Garaschuk
- Department of Neurophysiology, Institute of Physiology, University of Tübingen, 72074 Tübingen, Germany;
| |
Collapse
|
|
6
|
Mohd Khair SZN, Abd Radzak SM, Mohamed Yusoff AA. The Uprising of Mitochondrial DNA Biomarker in Cancer. DISEASE MARKERS 2021; 2021:7675269. [PMID: 34326906 PMCID: PMC8302403 DOI: 10.1155/2021/7675269] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 12/18/2022]
Abstract
Cancer is a heterogeneous group of diseases, the progression of which demands an accumulation of genetic mutations and epigenetic alterations of the human nuclear genome or possibly in the mitochondrial genome as well. Despite modern diagnostic and therapeutic approaches to battle cancer, there are still serious concerns about the increase in death from cancer globally. Recently, a growing number of researchers have extensively focused on the burgeoning area of biomarkers development research, especially in noninvasive early cancer detection. Intergenomic cross talk has triggered researchers to expand their studies from nuclear genome-based cancer researches, shifting into the mitochondria-mediated associations with carcinogenesis. Thus, it leads to the discoveries of established and potential mitochondrial biomarkers with high specificity and sensitivity. The research field of mitochondrial DNA (mtDNA) biomarkers has the great potential to confer vast benefits for cancer therapeutics and patients in the future. This review seeks to summarize the comprehensive insights of nuclear genome cancer biomarkers and their usage in clinical practices, the intergenomic cross talk researches that linked mitochondrial dysfunction to carcinogenesis, and the current progress of mitochondrial cancer biomarker studies and development.
Collapse
Affiliation(s)
- Siti Zulaikha Nashwa Mohd Khair
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Siti Muslihah Abd Radzak
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia
| |
Collapse
|
|
7
|
Schank M, Zhao J, Moorman JP, Yao ZQ. The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging. Cells 2021; 10:cells10010174. [PMID: 33467074 PMCID: PMC7830696 DOI: 10.3390/cells10010174] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 02/07/2023] Open
Abstract
According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.
Collapse
Affiliation(s)
- Madison Schank
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Juan Zhao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Jonathan P. Moorman
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
- Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA
| | - Zhi Q. Yao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (M.S.); (J.Z.); (J.P.M.)
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
- Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA
- Correspondence: ; Tel.: +423-439-8063; Fax: +423-439-7010
| |
Collapse
|
|
8
|
Villavicencio KM, Ahmed N, Harris ML, Singh KK. Mitochondrial DNA-depleter mouse as a model to study human pigmentary skin disorders. Pigment Cell Melanoma Res 2021; 34:179-187. [PMID: 33448673 DOI: 10.1111/pcmr.12921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/07/2020] [Accepted: 08/10/2020] [Indexed: 01/31/2023]
Abstract
Pigmentation abnormalities are reported in the spectrum of phenotypes associated with aging and in patients with mitochondrial DNA depletion syndrome (MDS). Yet, a relevant animal model that mimics these effects and would allow us to evaluate the detrimental aspects of mtDNA depletion on melanocyte function has not been described. Here, we characterize the pigmentary changes observed in the ears of a mtDNA-depleter mouse, which phenotypically includes accentuation of the peri-adnexal pseudonetwork, patchy hyper- and hypopigmentation, and reticular pigmentation. Histologically, these mice show increased epidermal pigmentation with patchy distribution, along with increased and highly dendritic melanocytes. These mtDNA-depleter mice mimic aspects of the cutaneous, pigmentary changes observed in humans with age-related senile lentigines as well as MDS. We suggest that this mouse model can serve as a novel resource for future interrogations of how mitochondrial dysfunction contributes to pigmentary skin disorders. The mtDNA-depleter mouse model also serves as a useful tool to identify novel agents capable of treating pigmentary changes associated with age-related mitochondrial dysfunction in humans.
Collapse
Affiliation(s)
| | - Noha Ahmed
- Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Dermatology, Zagazig University, Zagazig, Egypt
| | - Melissa L Harris
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Keshav K Singh
- Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| |
Collapse
|
|
9
|
Datta A, Alam MJ, Khaleda L, Al-Forkan M. Protective effects of Corchorus olitorius and Butea monosperma against Arsenic induced aberrant methylation and mitochondrial DNA damage in wistar rat model. Toxicol Rep 2021; 8:30-37. [PMID: 33391994 PMCID: PMC7772721 DOI: 10.1016/j.toxrep.2020.12.017] [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: 09/04/2020] [Revised: 11/07/2020] [Accepted: 12/16/2020] [Indexed: 11/26/2022] Open
Abstract
Arsenic exposure through food causes genotoxic effects in vivo. Sub chronic exposure to Arsenic causes pre-cancerous changes. C. olitorious & B. monosperma have significant nephro & hepato protective potential. Protective effect of both plants species is evident in molecular level. Potent use as readily available food supplement to minimize Arsenic toxicity. Millions of people around the world are chronically exposed to Arsenic (As) through food and drinking water. Studies revealed that Arsenic is genotoxic and causes damage to DNA. In this study, we evaluated Corchorus olitorius and Butea monosperma for their alleviative properties against Arsenic induced genotoxicity in vivo using Wistar Rat model. Arsenic exposed rats were given C. olitorius leaf powder and B. monosperma flower powder as supplementation with normal food. Methylation status of p53 promoter was measured using Methylation Sensitive Restriction Endonuclease PCR (MSRE-PCR) assay and mitochondrial DNA (mtDNA) copy number as well as occurrence of a common deletion in mtDNA in liver and kidney tissue was determined through quantitative realtime PCR (qPCR). Arsenic exposed rats after supplementation showed relatively less severe effects of toxicity evident by significantly higher amount of (p<0.05) mtDNA copy number and reduced occurrence of deletion containing mtDNA as well as lower levels of methylation in p53 gene promoter. Histopathological analysis revealed less severe histopathological changes of liver and kidney and normal liver and kidney function parameters in supplemented rats. So, the protective properties of B. monosperma and C. olitorius against Arsenic toxicity is evident in molecular level.
Collapse
Affiliation(s)
- Amit Datta
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, 4331, Bangladesh
| | - Md Jibran Alam
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, 4331, Bangladesh
| | - Laila Khaleda
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, 4331, Bangladesh
| | - Mohammad Al-Forkan
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, 4331, Bangladesh
| |
Collapse
|
|
10
|
Lee HJ, Lee SH, Lee JH, Kim Y, Seong KM, Jin YW, Min KJ. Role of Commensal Microbes in the γ-Ray Irradiation-Induced Physiological Changes in Drosophila melanogaster. Microorganisms 2020; 9:microorganisms9010031. [PMID: 33374132 PMCID: PMC7824294 DOI: 10.3390/microorganisms9010031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/29/2022] Open
Abstract
Ionizing radiation induces biological/physiological changes and affects commensal microbes, but few studies have examined the relationship between the physiological changes induced by irradiation and commensal microbes. This study investigated the role of commensal microbes in the γ-ray irradiation-induced physiological changes in Drosophila melanogaster. The bacterial load was increased in 5 Gy irradiated flies, but irradiation decreased the number of operational taxonomic units. The mean lifespan of conventional flies showed no significant change by irradiation, whereas that of axenic flies was negatively correlated with the radiation dose. γ-Ray irradiation did not change the average number of eggs in both conventional and axenic flies. Locomotion of conventional flies was decreased after 5 Gy radiation exposure, whereas no significant change in locomotion activity was detected in axenic flies after irradiation. γ-Ray irradiation increased the generation of reactive oxygen species in both conventional and axenic flies, but the increase was higher in axenic flies. Similarly, the amounts of mitochondria were increased in irradiated axenic flies but not in conventional flies. These results suggest that axenic flies are more sensitive in their mitochondrial responses to radiation than conventional flies, and increased sensitivity leads to a reduced lifespan and other physiological changes in axenic flies.
Collapse
Affiliation(s)
- Hwa-Jin Lee
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
| | - Shin-Hae Lee
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
| | - Ji-Hyeon Lee
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
| | - Yongjoong Kim
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (Y.K.); (K.M.S.); (Y.W.J.)
| | - Ki Moon Seong
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (Y.K.); (K.M.S.); (Y.W.J.)
| | - Young Woo Jin
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (Y.K.); (K.M.S.); (Y.W.J.)
| | - Kyung-Jin Min
- Department of Biological Sciences, Inha University, Incheon 22212, Korea; (H.-J.L.); (S.-H.L.); (J.-H.L.)
- Correspondence:
| |
Collapse
|
|
11
|
Placental function in maternal obesity. Clin Sci (Lond) 2020; 134:961-984. [PMID: 32313958 DOI: 10.1042/cs20190266] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023]
Abstract
Maternal obesity is associated with pregnancy complications and increases the risk for the infant to develop obesity, diabetes and cardiovascular disease later in life. However, the mechanisms linking the maternal obesogenic environment to adverse short- and long-term outcomes remain poorly understood. As compared with pregnant women with normal BMI, women entering pregnancy obese have more pronounced insulin resistance, higher circulating plasma insulin, leptin, IGF-1, lipids and possibly proinflammatory cytokines and lower plasma adiponectin. Importantly, the changes in maternal levels of nutrients, growth factors and hormones in maternal obesity modulate placental function. For example, high insulin, leptin, IGF-1 and low adiponectin in obese pregnant women activate mTOR signaling in the placenta, promoting protein synthesis, mitochondrial function and nutrient transport. These changes are believed to increase fetal nutrient supply and contribute to fetal overgrowth and/or adiposity in offspring, which increases the risk to develop disease later in life. However, the majority of obese women give birth to normal weight infants and these pregnancies are also associated with activation of inflammatory signaling pathways, oxidative stress, decreased oxidative phosphorylation and lipid accumulation in the placenta. Recent bioinformatics approaches have expanded our understanding of how maternal obesity affects the placenta; however, the link between changes in placental function and adverse outcomes in obese women giving birth to normal sized infants is unclear. Interventions that specifically target placental function, such as activation of placental adiponectin receptors, may prevent the transmission of metabolic disease from obese women to the next generation.
Collapse
|
|
12
|
Das S, Joshi MB, Parashiva GK, Rao SBS. Stimulation of cytoprotective autophagy and components of mitochondrial biogenesis / proteostasis in response to ionizing radiation as a credible pro-survival strategy. Free Radic Biol Med 2020; 152:715-727. [PMID: 31968231 DOI: 10.1016/j.freeradbiomed.2020.01.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 01/14/2020] [Accepted: 01/14/2020] [Indexed: 12/11/2022]
Abstract
The present study illustrates mitochondria-mediated impact of ionizing radiation which is paralleled by activation of several pro-adaptive responses in normal human dermal fibroblast cells. Irradiation of cells with X-rays (5 Gy) led to an increase in fragmentation and mitochondrial mass. Distinct temporal changes in cytosolic and mitochondrial reactive oxygen species (ROS) were noted in response to radiation, which was associated with depletion in mitochondrial membrane potential followed by decrease in ATP levels. Long Amplicon-Polymerase Chain Reaction (LA-PCR) analysis showed time-dependent increase in mitochondrial DNA damage that preceded mitochondrial ROS generation. Irradiation of cells led to an initial G2/M arrest at 8 h that persisted till 16 h, with subsequent block at G0/G1 measured at 48 and 72 h time points. Interestingly, cells activated autophagy as a countermeasure against radiation-mediated cellular insults and aided in removal of damaged mitochondria. Blocking autophagy using 3-methyladenine led to cell death via activation of enhanced ROS, PARP-1 and caspase 3 cleavage. Upregulation of mitochondrial biogenesis factors Nrf1/PGC-1α, following irradiation was observed. Irradiated cells exhibited an increase in the phosphorylation of GCN2, PERK and eIF2α that might be responsible for the up-regulation of ATF4 and CHOP thereby regulating autophagy and components of integrated stress response. Apart from this, we measured accumulation of mitochondrial chaperones (HSP60/HSP10) and ATF5 which is a major molecule involved in mitochondrial stress. Taken together, mitochondria are one of the major cytoplasmic targets for ionizing radiation and possibly act as an early indicator of cellular insult. The findings also show that stressed mitochondria might influence endoplasmic reticulum (ER)-related signalling leading to the activation of adaptive mechanisms like cytoprotective autophagy, and molecules responsible for mitochondrial biogenesis and protein quality control in order to replenish mitochondrial pool and maintain cellular homeostasis.
Collapse
Affiliation(s)
- Shubhankar Das
- Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Manjunath B Joshi
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Guruprasad K Parashiva
- Department of Aging Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Satish B S Rao
- Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
| |
Collapse
|
|
13
|
Anderson AP, Luo X, Russell W, Yin YW. Oxidative damage diminishes mitochondrial DNA polymerase replication fidelity. Nucleic Acids Res 2020; 48:817-829. [PMID: 31799610 PMCID: PMC6954441 DOI: 10.1093/nar/gkz1018] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 10/12/2019] [Accepted: 11/22/2019] [Indexed: 12/20/2022] Open
Abstract
Mitochondrial DNA (mtDNA) resides in a high ROS environment and suffers more mutations than its nuclear counterpart. Increasing evidence suggests that mtDNA mutations are not the results of direct oxidative damage, rather are caused, at least in part, by DNA replication errors. To understand how the mtDNA replicase, Pol γ, can give rise to elevated mutations, we studied the effect of oxidation of Pol γ on replication errors. Pol γ is a high fidelity polymerase with polymerase (pol) and proofreading exonuclease (exo) activities. We show that Pol γ exo domain is far more sensitive to oxidation than pol; under oxidative conditions, exonuclease activity therefore declines more rapidly than polymerase. The oxidized Pol γ becomes editing-deficient, displaying a 20-fold elevated mutations than the unoxidized enzyme. Mass spectrometry analysis reveals that Pol γ exo domain is a hotspot for oxidation. The oxidized exo residues increase the net negative charge around the active site that should reduce the affinity to mismatched primer/template DNA. Our results suggest that the oxidative stress induced high mutation frequency on mtDNA can be indirectly caused by oxidation of the mitochondrial replicase.
Collapse
Affiliation(s)
- Andrew P Anderson
- Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA
- Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Xuemei Luo
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77550, USA
| | - William Russell
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Y Whitney Yin
- Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, TX 77550, USA
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77550, USA
| |
Collapse
|
|
14
|
Hsieh FI, Chiou HY, Hu CJ, Jeng JS, Lin HJ, Lee JT, Lien LM. Combined Effects of MMP-7, MMP-8 and MMP-26 on the Risk of Ischemic Stroke. J Clin Med 2019; 8:jcm8112011. [PMID: 31752174 PMCID: PMC6912324 DOI: 10.3390/jcm8112011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 10/31/2019] [Accepted: 11/11/2019] [Indexed: 12/16/2022] Open
Abstract
Ischemic stroke (IS) is multifactorial causation combining with traditional cardiovascular disease (CVD) and genetic risk factors. Combined effects of MMP-7, MMP-8 and MMP-26 on the risk of IS remain incompletely understood. We aimed to assess individual and joint effects for IS risk by weighted genetic risk score (wGRS) from these three genes and traditional CVD risk factors. A case-control study including 500 cases with IS and 500 stroke-free healthy controls frequency-matched with cases by age and sex was conducted. The wGRS was a weighted average of the number of risk genotype across selected SNPs from MMP-7, MMP-8 and MMP-26. Multivariate logistic regression models were used to analyze the relationship between wGRS and risk of IS. A wGRS in the second tertile was associated with a 1.5-fold increased risk of IS compared with the lowest tertile after adjusting for traditional CVD risk factors. Compared to subjects with low genetic and low modifiable CVD risk, those with high genetic and high modifiable CVD risk had the highest risk of IS (adjusted-OR = 5.75). In conclusion, higher wGRS was significantly associated with an increased risk for IS. A significant interaction between genetic and traditional CVD risk factors was also found on the risk of IS.
Collapse
Affiliation(s)
- Fang-I Hsieh
- School of Public Health, College of Public Health, Taipei Medical University, Taipei 110, Taiwan; (F.-I.H.); (H.-Y.C.)
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
| | - Hung-Yi Chiou
- School of Public Health, College of Public Health, Taipei Medical University, Taipei 110, Taiwan; (F.-I.H.); (H.-Y.C.)
| | - Chaur-Jong Hu
- Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan;
| | - Jiann-Shing Jeng
- Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan;
| | - Huey-Juan Lin
- Department of Neurology, Chi-Mei Medical Center, Tainan 710, Taiwan;
| | - Jiunn-Tay Lee
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan;
| | - Li-Ming Lien
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
- Correspondence:
| |
Collapse
|
|
15
|
Kauppila JHK, Bonekamp NA, Mourier A, Isokallio MA, Just A, Kauppila TES, Stewart JB, Larsson NG. Base-excision repair deficiency alone or combined with increased oxidative stress does not increase mtDNA point mutations in mice. Nucleic Acids Res 2019; 46:6642-6669. [PMID: 29860357 PMCID: PMC6061787 DOI: 10.1093/nar/gky456] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 05/11/2018] [Indexed: 12/19/2022] Open
Abstract
Mitochondrial DNA (mtDNA) mutations become more prevalent with age and are postulated to contribute to the ageing process. Point mutations of mtDNA have been suggested to originate from two main sources, i.e. replicative errors and oxidative damage, but the contribution of each of these processes is much discussed. To elucidate the origin of mtDNA mutations, we measured point mutation load in mice with deficient mitochondrial base-excision repair (BER) caused by knockout alleles preventing mitochondrial import of the DNA repair glycosylases OGG1 and MUTYH (Ogg1 dMTS, Mutyh dMTS). Surprisingly, we detected no increase in the mtDNA mutation load in old Ogg1 dMTS mice. As DNA repair is especially important in the germ line, we bred the BER deficient mice for five consecutive generations but found no increase in the mtDNA mutation load in these maternal lineages. To increase reactive oxygen species (ROS) levels and oxidative damage, we bred the Ogg1 dMTS mice with tissue specific Sod2 knockout mice. Although increased superoxide levels caused a plethora of changes in mitochondrial function, we did not detect any changes in the mutation load of mtDNA or mtRNA. Our results show that the importance of oxidative damage as a contributor of mtDNA mutations should be re-evaluated.
Collapse
Affiliation(s)
- Johanna H K Kauppila
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Nina A Bonekamp
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Arnaud Mourier
- Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, Bordeaux, France
| | - Marita A Isokallio
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Alexandra Just
- FACS & Imaging Core Facility, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Timo E S Kauppila
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - James B Stewart
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Nils-Göran Larsson
- Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne, Germany.,Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
16
|
DNA polymerase-γ hypothesis in nucleoside reverse transcriptase-induced mitochondrial toxicity revisited: A potentially protective role for citrus fruit-derived naringenin? Eur J Pharmacol 2019; 852:159-166. [PMID: 30876974 DOI: 10.1016/j.ejphar.2019.03.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/11/2019] [Accepted: 03/11/2019] [Indexed: 12/23/2022]
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) form the backbone in combination antiretroviral therapy (cARVs). They halt chain elongation of the viral cDNA by acting as false substrates in counterfeit incorporation mechanism to viral RNA-dependent DNA polymerase. In the process genomic DNA polymerase as well as mitochondrial DNA (mtDNA) polymerase-γ (which has a much higher affinity for these drugs at therapeutic doses) are also impaired. This leads to mitochondrial toxicity that manifests clinically as mitochondrial myopathy, peripheral neuropathy, hyperlactatemia or lactic acidosis and lipoatrophy. This has led to the revision of clinical guidelines by World Health Organization to remove stavudine from first-line listing in the treatment of HIV infections. Recent reports have implicated oxidative stress besides mtDNA polymerase-γ hypothesis in NRTI-induced metabolic complications. Reduced plasma antioxidant concentrations have been reported in HIV positive patients on cARVs but clinical intervention with antioxidant supplements have not been successful either due to low efficacy or poor experimental designs. Citrus fruit-derived naringenin has previously been demonstrated to possess antioxidant and free radical scavenging properties which could prevent mitochondrial toxicity associated with these drugs. This review revisits the controversy surrounding mtDNA polymerase-γ hypothesis and evaluates the potential benefits of naringenin as a potent anti-oxidant and free radical scavenger which as a nutritional supplement or therapeutic adjunct could mitigate the development of mitochondrial toxicity associated with these drugs.
Collapse
|
|
17
|
Fazzini F, Lamina C, Fendt L, Schultheiss UT, Kotsis F, Hicks AA, Meiselbach H, Weissensteiner H, Forer L, Krane V, Eckardt KU, Köttgen A, Kronenberg F. Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease. Kidney Int 2019; 96:480-488. [PMID: 31248648 DOI: 10.1016/j.kint.2019.04.021] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/29/2019] [Accepted: 04/05/2019] [Indexed: 12/16/2022]
Abstract
Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.
Collapse
Affiliation(s)
- Federica Fazzini
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Claudia Lamina
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Liane Fendt
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Ulla T Schultheiss
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Renal Division, Department of Medicine IV, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Fruzsina Kotsis
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Andrew A Hicks
- Institute for Biomedicine, EURAC Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
| | - Heike Meiselbach
- Department of Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Hansi Weissensteiner
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Lukas Forer
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Vera Krane
- Division of Nephrology, Department of Internal Medicine I, Division of Nephrology and Comprehensive Heart Failure Centre, University Hospital Würzburg, Würzburg, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Florian Kronenberg
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
| | | |
Collapse
|
|
18
|
Sárközy M, Kovács ZZA, Kovács MG, Gáspár R, Szűcs G, Dux L. Mechanisms and Modulation of Oxidative/Nitrative Stress in Type 4 Cardio-Renal Syndrome and Renal Sarcopenia. Front Physiol 2018; 9:1648. [PMID: 30534079 PMCID: PMC6275322 DOI: 10.3389/fphys.2018.01648] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 10/31/2018] [Indexed: 12/12/2022] Open
Abstract
Chronic kidney disease (CKD) is a public health problem and a recognized risk factor for cardiovascular diseases (CVD). CKD could amplify the progression of chronic heart failure leading to the development of type 4 cardio-renal syndrome (T4CRS). The severity and persistence of heart failure are strongly associated with mortality risk in T4CRS. CKD is also a catabolic state leading to renal sarcopenia which is characterized by the loss of skeletal muscle strength and physical function. Renal sarcopenia also promotes the development of CVD and increases the mortality in CKD patients. In turn, heart failure developed in T4CRS could result in chronic muscle hypoperfusion and metabolic disturbances leading to or aggravating the renal sarcopenia. The interplay of multiple factors (e.g., comorbidities, over-activated renin-angiotensin-aldosterone system [RAAS], sympathetic nervous system [SNS], oxidative/nitrative stress, inflammation, etc.) may result in the progression of T4CRS and renal sarcopenia. Among these factors, oxidative/nitrative stress plays a crucial role in the complex pathomechanism and interrelationship between T4CRS and renal sarcopenia. In the heart and skeletal muscle, mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, uncoupled nitric oxide synthase (NOS) and xanthine oxidase are major ROS sources producing superoxide anion (O2·−) and/or hydrogen peroxide (H2O2). O2·− reacts with nitric oxide (NO) forming peroxynitrite (ONOO−) which is a highly reactive nitrogen species (RNS). High levels of ROS/RNS cause lipid peroxidation, DNA damage, interacts with both DNA repair enzymes and transcription factors, leads to the oxidation/nitration of key proteins involved in contractility, calcium handling, metabolism, antioxidant defense mechanisms, etc. It also activates the inflammatory response, stress signals inducing cardiac hypertrophy, fibrosis, or cell death via different mechanisms (e.g., apoptosis, necrosis) and dysregulates autophagy. Therefore, the thorough understanding of the mechanisms which lead to perturbations in oxidative/nitrative metabolism and its relationship with pro-inflammatory, hypertrophic, fibrotic, cell death and other pathways would help to develop strategies to counteract systemic and tissue oxidative/nitrative stress in T4CRS and renal sarcopenia. In this review, we also focus on the effects of some well-known and novel pharmaceuticals, nutraceuticals, and physical exercise on cardiac and skeletal muscle oxidative/nitrative stress in T4CRS and renal sarcopenia.
Collapse
Affiliation(s)
- Márta Sárközy
- Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Zsuzsanna Z A Kovács
- Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Mónika G Kovács
- Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Renáta Gáspár
- Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - Gergő Szűcs
- Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary
| | - László Dux
- Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary
| |
Collapse
|
|
19
|
Dhar SK, Bakthavatchalu V, Dhar B, Chen J, Tadahide I, Zhu H, Gao T, St Clair DK. DNA polymerase gamma (Polγ) deficiency triggers a selective mTORC2 prosurvival autophagy response via mitochondria-mediated ROS signaling. Oncogene 2018; 37:6225-6242. [PMID: 30038268 PMCID: PMC6265263 DOI: 10.1038/s41388-018-0404-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 04/30/2018] [Accepted: 06/11/2018] [Indexed: 11/24/2022]
Abstract
Autophagy is a highly regulated evolutionarily conserved metabolic process induced by stress and energy deprivation. Here, we show that DNA polymerase gamma (Polγ) deficiency activates a selective prosurvival autophagic response via mitochondria-mediated reactive oxygen species (ROS) signaling and the mammalian target of rapamycin complex 2 (mTORC2) activities. In keratinocytes, Polγ deficiency causes metabolic adaptation that triggers cytosolic sensing of energy demand for survival. Knockdown of Polγ causes mitochondrial stress, decreases mitochondrial energy production, increases glycolysis, increases the expression of autophagy-associated genes, and enhances AKT phosphorylation and cell proliferation. Deficiency of Polγ preferentially activates mTORC2 formation to increase autophagy and cell proliferation, and knocking down Rictor abrogates these responses. Overexpression of Rictor, but not Raptor, reactivates autophagy in Polγ-deficient cells. Importantly, inhibition of ROS by a mitochondria-selective ROS scavenger abolishes autophagy and cell proliferation. These results identify Rictor as a critical link between mitochondrial stress, ROS, and autophagy. They represent a major shift in our understanding of the prosurvival role of the mTOR complexes and highlight mitochondria-mediated ROS as a prosurvival autophagy regulator during cancer development.
Collapse
Affiliation(s)
- Sanjit K Dhar
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Vasudevan Bakthavatchalu
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Bithika Dhar
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Jing Chen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA
| | - Izumi Tadahide
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA
| | - Haining Zhu
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA
| | - Tianyan Gao
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA
| | - Daret K St Clair
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA.
| |
Collapse
|
|
20
|
Lien LM, Chiou HY, Yeh HL, Chiu SY, Jeng JS, Lin HJ, Hu CJ, Hsieh FI, Wei YH. Significant Association Between Low Mitochondrial DNA Content in Peripheral Blood Leukocytes and Ischemic Stroke. J Am Heart Assoc 2017; 6:JAHA.117.006157. [PMID: 29151031 PMCID: PMC5721740 DOI: 10.1161/jaha.117.006157] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Background Cumulative evidence has shown that low mitochondrial DNA (mtDNA) content is related to elevated oxidative stress and atherosclerosis, which play important roles in ischemic stroke. The objective of this study was to explore the association between mtDNA content in peripheral blood leukocytes and ischemic stroke. Methods and Results A total of 350 patients with first‐ever ischemic stroke and 350 healthy controls were recruited in this case‐control study. The mtDNA content in peripheral blood leukocytes was determined by quantitative real‐time polymerase chain reaction. The levels of oxidized glutathione, reduced glutathione, and 8‐hydroxy‐2′‐deoxyguanosine were measured by ELISA kits. Multivariate logistic regression models were used to analyze the relationship between mtDNA content in peripheral blood leukocytes and ischemic stroke. Our results show that mtDNA content of patients with ischemic stroke was notably lower compared with controls. A significant association was found between low mtDNA content and ischemic stroke. Furthermore, significant interactions were identified between low mtDNA and proven risk factors in patients with ischemic stroke. The levels of oxidized glutathione and 8‐hydroxy‐2′‐deoxyguanosine were significantly greater in patients with ischemic stroke compared with controls. Conclusions Our results demonstrate that low mtDNA content in peripheral blood leukocytes is associated with ischemic stroke. The relationship of low mtDNA content and ischemic stroke was particularly notable in individuals who had low mtDNA content combined with diabetes mellitus, metabolic syndrome, or cigarette smoking. Oxidative stress may be one of the contributory factors to decreased mtDNA content in patients with ischemic stroke.
Collapse
Affiliation(s)
- Li-Ming Lien
- Department of Neurology, Shin-Kong WHS Memorial Hospital, Taipei, Taiwan.,School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hung-Yi Chiou
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Hsu-Ling Yeh
- Department of Neurology, Shin-Kong WHS Memorial Hospital, Taipei, Taiwan.,School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shang-Yen Chiu
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Jiann-Shing Jeng
- Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Juan Lin
- Department of Neurology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Chaur-Jong Hu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Fang-I Hsieh
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Yau-Huei Wei
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.,Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, Changhua City, Taiwan
| |
Collapse
|
|
21
|
Smith RL, Tan JME, Jonker MJ, Jongejan A, Buissink T, Veldhuijzen S, van Kampen AHC, Brul S, van der Spek H. Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity. PLoS One 2017; 12:e0187424. [PMID: 29095935 PMCID: PMC5667870 DOI: 10.1371/journal.pone.0187424] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 10/19/2017] [Indexed: 12/17/2022] Open
Abstract
Use of some HIV-1 nucleoside reverse transcriptase inhibitors (NRTI) is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to specific NRTIs has predominantly been assigned to mitochondrial polymerase-γ inhibition by NRTIs. However, an increasing amount of data suggests that this is not the sole mechanism. Many NRTI induced adverse events have been linked to the incurrence of oxidative stress, although the causality of events leading to reactive oxygen species (ROS) production and their role in toxicity is unclear. In this study we show that short-term effects of first generation NRTIs, which are rarely discussed in the literature, include inhibition of oxygen consumption, decreased ATP levels and increased ROS production. Collectively these events affect fitness and longevity of C. elegans through mitohormetic signalling events. Furthermore, we demonstrate that these effects can be normalized by addition of the anti-oxidant N-acetylcysteine (NAC), which suggests that ROS likely influence the onset and severity of adverse events upon drug exposure.
Collapse
Affiliation(s)
- Reuben L. Smith
- Molecular Biology & Microbial Food Safety, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| | - Josephine M. E. Tan
- Molecular Biology & Microbial Food Safety, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| | - Martijs J. Jonker
- RNA Biology & Applied Bioinformatics, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| | - Aldo Jongejan
- Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - Thomas Buissink
- Molecular Biology & Microbial Food Safety, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| | - Steve Veldhuijzen
- Molecular Biology & Microbial Food Safety, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| | - Antoine H. C. van Kampen
- Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center (AMC), Amsterdam, The Netherlands
- Biosystems data analysis, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| | - Stanley Brul
- Molecular Biology & Microbial Food Safety, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| | - Hans van der Spek
- Molecular Biology & Microbial Food Safety, Swammerdam Institute for Life Sciences (SILS), Faculty of Science (FNWI), University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
22
|
Errichiello E, Venesio T. Mitochondrial DNA variants in colorectal carcinogenesis: Drivers or passengers? J Cancer Res Clin Oncol 2017; 143:1905-1914. [PMID: 28393270 DOI: 10.1007/s00432-017-2418-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 04/03/2017] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Mitochondrial DNA alterations have widely been reported in many age-related degenerative diseases and tumors, including colorectal cancer. In the past few years, the discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. FINDINGS Mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. Mitochondrial DNA alterations include point mutations, deletions, inversions, and copy number variations, but numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, the biological impact of mitochondrial DNA variants may vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (heteroplasmy). CONCLUSIONS In this review, we discuss the role of different type of mitochondrial DNA alterations in colorectal carcinogenesis and, in particular, we revisit the issue of whether they may be considered as causative driver or simply genuine passenger events. The advent of high-throughput techniques as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in colorectal cancer are also explored.
Collapse
Affiliation(s)
- Edoardo Errichiello
- Department of Molecular Medicine, University of Pavia, Via Forlanini 14, 27100, Pavia, Italy.
- Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Starda Provinciale 142, Candiolo, 10060, Turin, Italy.
| | - Tiziana Venesio
- Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Starda Provinciale 142, Candiolo, 10060, Turin, Italy
| |
Collapse
|
|
23
|
Mohamed Yusoff AA, Mohd Nasir KN, Haris K, Mohd Khair SZN, Abdul Ghani ARI, Idris Z, Abdullah JM. Detection of somatic mutations in the mitochondrial DNA control region D-loop in brain tumors: The first report in Malaysian patients. Oncol Lett 2017; 14:5179-5188. [PMID: 29098023 PMCID: PMC5652220 DOI: 10.3892/ol.2017.6851] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Accepted: 05/11/2017] [Indexed: 01/01/2023] Open
Abstract
Although the role of nuclear-encoded gene alterations has been well documented in brain tumor development, the involvement of the mitochondrial genome in brain tumorigenesis has not yet been fully elucidated and remains controversial. The present study aimed to identify mutations in the mitochondrial DNA (mtDNA) control region D-loop in patients with brain tumors in Malaysia. A mutation analysis was performed in which DNA was extracted from paired tumor tissue and blood samples obtained from 49 patients with brain tumors. The D-loop region DNA was amplified using the PCR technique, and genetic data from DNA sequencing analyses were compared with the published revised Cambridge sequence to identify somatic mutations. Among the 49 brain tumor tissue samples evaluated, 25 cases (51%) had somatic mutations of the mtDNA D-loop, with a total of 48 mutations. Novel mutations that had not previously been identified in the D-loop region (176 A-deletion, 476 C>A, 566 C>A and 16405 A-deletion) were also classified. No significant associations between the D-loop mutation status and the clinicopathological parameters were observed. To the best of our knowledge, the current study presents the first evidence of alterations in the mtDNA D-loop regions in the brain tumors of Malaysian patients. These results may provide an overview and data regarding the incidence of mitochondrial genome alterations in Malaysian patients with brain tumors. In addition to nuclear genome aberrations, these specific mitochondrial genome alterations may also be considered as potential cancer biomarkers for the diagnosis and staging of brain cancers.
Collapse
Affiliation(s)
- Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Khairol Naaim Mohd Nasir
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Khalilah Haris
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Siti Zulaikha Nashwa Mohd Khair
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Abdul Rahman Izaini Abdul Ghani
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Zamzuri Idris
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia.,Center for Neuroscience Services and Research, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| | - Jafri Malin Abdullah
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia.,Center for Neuroscience Services and Research, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan 16150, Malaysia
| |
Collapse
|
|
24
|
Chan SSL. Inherited mitochondrial genomic instability and chemical exposures. Toxicology 2017; 391:75-83. [PMID: 28756246 DOI: 10.1016/j.tox.2017.07.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/12/2017] [Accepted: 07/24/2017] [Indexed: 12/21/2022]
Abstract
There are approximately 1500 proteins that are needed for mitochondrial structure and function, most of which are encoded in the nuclear genome (Calvo et al., 2006). Each mitochondrion has its own genome (mtDNA), which in humans encodes 13 polypeptides, 22 tRNAs and 2 rRNAs required for oxidative phosphorylation. The mitochondrial genome of humans and most vertebrates is approximately 16.5kbp, double-stranded, circular, with few non-coding bases. Thus, maintaining mtDNA stability, that is, the ability of the cell to maintain adequate levels of mtDNA template for oxidative phosphorylation is essential and can be impacted by the level of mtDNA mutation currently within the cell or mitochondrion, but also from errors made during normal mtDNA replication, defects in mitochondrial quality control mechanisms, and exacerbated by exposures to exogenous and/or endogenous genotoxic agents. In this review, we expand on the origins and consequences of mtDNA instability, the current state of research regarding the mechanisms by which mtDNA instability can be overcome by cellular and chemical interventions, and the future of research and treatments for mtDNA instability.
Collapse
Affiliation(s)
- Sherine S L Chan
- Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States; Neuroene Therapeutics, Mt. Pleasant, SC 29464, United States.
| |
Collapse
|
|
25
|
Tamrin SH, Majedi FS, Tondar M, Sanati-Nezhad A, Hasani-Sadrabadi MM. Electromagnetic Fields and Stem Cell Fate: When Physics Meets Biology. Rev Physiol Biochem Pharmacol 2017; 171:63-97. [PMID: 27515674 DOI: 10.1007/112_2016_4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Controlling stem cell (SC) fate is an extremely important topic in the realm of SC research. A variety of different external cues mainly mechanical, chemical, or electrical stimulations individually or in combination have been incorporated to control SC fate. Here, we will deconstruct the probable relationship between the functioning of electromagnetic (EMF) and SC fate of a variety of different SCs. The electromagnetic (EM) nature of the cells is discussed with the emphasis on the effects of EMF on the determinant factors that directly and/or indirectly influence cell fate. Based on the EM effects on a variety of cellular processes, it is believed that EMFs can be engineered to provide a controlled signal with the highest impact on the SC fate decision. Considering the novelty and broad applications of applying EMFs to change SC fate, it is necessary to shed light on many unclear mechanisms underlying this phenomenon.
Collapse
Affiliation(s)
- Sara Hassanpour Tamrin
- Center of Excellence in Biomaterials, Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran
| | | | - Mahdi Tondar
- Department of Biochemistry and Molecular & Cellular Biology, School of Medicine, Georgetown University, Washington, DC, USA
| | - Amir Sanati-Nezhad
- BioMEMS and BioInspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, Center for Bioengineering Research and Education, University of Calgary, Calgary, AB, Canada, T2N1N4.
| | - Mohammad Mahdi Hasani-Sadrabadi
- Department of Chemistry & Biochemistry, and California NanoSystems Institute, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
- Parker H. Petit Institute for Bioengineering and Bioscience and G.W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
| |
Collapse
|
|
26
|
Wang L. Mitochondrial purine and pyrimidine metabolism and beyond. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2017; 35:578-594. [PMID: 27906631 DOI: 10.1080/15257770.2015.1125001] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Carefully balanced deoxynucleoside triphosphate (dNTP) pools are essential for both nuclear and mitochondrial genome replication and repair. Two synthetic pathways operate in cells to produce dNTPs, e.g., the de novo and the salvage pathways. The key regulatory enzymes for de novo synthesis are ribonucleotide reductase (RNR) and thymidylate synthase (TS), and this process is considered to be cytosolic. The salvage pathway operates both in the cytosol (TK1 and dCK) and the mitochondria (TK2 and dGK). Mitochondrial dNTP pools are separated from the cytosolic ones owing to the double membrane structure of the mitochondria, and are formed by the salvage enzymes TK2 and dGK together with NMPKs and NDPK in postmitotic tissues, while in proliferating cells the mitochondrial dNTPs are mainly imported from the cytosol produced by the cytosolic pathways. Imbalanced mitochondrial dNTP pools lead to mtDNA depletion and/or deletions resulting in serious mitochondrial diseases. The mtDNA depletion syndrome is caused by deficiencies not only in enzymes in dNTP synthesis (TK2, dGK, p53R2, and TP) and mtDNA replication (mtDNA polymerase and twinkle helicase), but also in enzymes in other metabolic pathways such as SUCLA2 and SUCLG1, ABAT and MPV17. Basic questions are why defects in these enzymes affect dNTP synthesis and how important is mitochondrial nucleotide synthesis in the whole cell/organism perspective? This review will focus on recent studies on purine and pyrimidine metabolism, which have revealed several important links that connect mitochondrial nucleotide metabolism with amino acids, glucose, and fatty acid metabolism.
Collapse
Affiliation(s)
- Liya Wang
- a Department of Anatomy, Physiology and Biochemistry , Swedish University of Agricultural Sciences , Uppsala , Sweden
| |
Collapse
|
|
27
|
Sun Y, Zong L, Gao Z, Zhu S, Tong J, Cao Y. Mitochondrial DNA damage and oxidative damage in HL-60 cells exposed to 900MHz radiofrequency fields. Mutat Res 2017; 797-799:7-14. [PMID: 28340409 DOI: 10.1016/j.mrfmmm.2017.03.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 03/03/2017] [Accepted: 03/03/2017] [Indexed: 11/16/2022]
Abstract
HL-60 cells, derived from human promyelocytic leukemia, were exposed to continuous wave 900MHz radiofrequency fields (RF) at 120μW/cm2 power intensity for 4h/day for 5 consecutive days to examine whether such exposure is capable damaging the mitochondrial DNA (mtDNA) mediated through the production of reactive oxygen species (ROS). In addition, the effect of RF exposure was examined on 8-hydroxy-2'-dexoyguanosine (8-OHdG) which is a biomarker for oxidative damage and on the mitochondrial synthesis of adenosine triphosphate (ATP) which is the energy required for cellular functions. The results indicated a significant increase in ROS and significant decreases in mitochondrial transcription factor A, mtDNA polymerase gamma, mtDNA transcripts and mtDNA copy number in RF-exposed cells compared with those in sham-exposed control cells. In addition, there was a significant increase in 8-OHdG and a significant decrease in ATP in RF-exposed cells. The response in positive control cells exposed to gamma radiation (GR, which is also known to induce ROS) was similar to those in RF-exposed cells. Thus, the overall data indicated that RF exposure was capable of inducing mtDNA damage mediated through ROS pathway which also induced oxidative damage. Prior-treatment of RF- and GR-exposed the cells with melatonin, a well-known free radical scavenger, reversed the effects observed in RF-exposed cells.
Collapse
Affiliation(s)
- Yulong Sun
- School of Public Health, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Lin Zong
- School of Public Health, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Zhen Gao
- School of Public Health, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Shunxing Zhu
- Laboratory Animal Center, Nantong University, Nantong, Jiangsu Province, PR China
| | - Jian Tong
- School of Public Health, Soochow University, Suzhou, Jiangsu Province, PR China
| | - Yi Cao
- School of Public Health, Soochow University, Suzhou, Jiangsu Province, PR China.
| |
Collapse
|
|
28
|
Figueira I, Fernandes A, Mladenovic Djordjevic A, Lopez-Contreras A, Henriques CM, Selman C, Ferreiro E, Gonos ES, Trejo JL, Misra J, Rasmussen LJ, Xapelli S, Ellam T, Bellantuono I. Interventions for age-related diseases: Shifting the paradigm. Mech Ageing Dev 2016; 160:69-92. [DOI: 10.1016/j.mad.2016.09.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 09/18/2016] [Accepted: 09/28/2016] [Indexed: 12/14/2022]
|
|
29
|
Tin A, Grams ME, Ashar FN, Lane JA, Rosenberg AZ, Grove ML, Boerwinkle E, Selvin E, Coresh J, Pankratz N, Arking DE. Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study. J Am Soc Nephrol 2016; 27:2467-73. [PMID: 26794963 DOI: 10.1681/asn.2015060661] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 11/30/2015] [Indexed: 11/03/2022] Open
Abstract
Mitochondrial dysfunction in kidney cells has been implicated in the pathogenesis of CKD. Mitochondrial DNA (mtDNA) copy number is a surrogate measure of mitochondrial function, and higher mtDNA copy number in peripheral blood has been associated with lower risk of two important risk factors for CKD progression, diabetes and microalbuminuria. We evaluated whether mtDNA copy number in peripheral blood associates with incident CKD in a population-based cohort of middle-aged adults. We estimated mtDNA copy number using 25 high-quality mitochondrial single nucleotide polymorphisms from the Affymetrix 6.0 array. Among 9058 participants, those with higher mtDNA copy number had a lower rate of prevalent diabetes and lower C-reactive protein levels and white blood cell counts. Baseline eGFR did not differ significantly by mtDNA copy number. Over a median follow-up of 19.6 years, 1490 participants developed CKD. Higher mtDNA copy number associated with lower risk of incident CKD (highest versus lowest quartile: hazard ratio 0.65; 95% confidence interval, 0.56 to 0.75; P<0.001) after adjusting for age, sex, and race. After adjusting for additional risk factors of CKD, including prevalent diabetes, hypertension, C-reactive protein level, and white blood cell count, this association remained significant (highest versus lowest quartile: hazard ratio 0.75; 95% confidence interval, 0.64 to 0.87; P<0.001). In conclusion, higher mtDNA copy number associated with lower incidence of CKD independent of traditional risk factors and inflammation biomarker levels in this cohort. Further research on modifiable factors influencing mtDNA copy number may lead to improvement in the prevention and treatment of CKD.
Collapse
Affiliation(s)
- Adrienne Tin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
| | | | - Foram N Ashar
- McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - John A Lane
- Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Avi Z Rosenberg
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Federick, Maryland; Children's National Medical Center, Washington, DC; and
| | - Megan L Grove
- Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Eric Boerwinkle
- Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Nathan Pankratz
- Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Dan E Arking
- McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
30
|
Apoptosis or autophagy, that is the question: Two ways for muscle sacrifice towards meat. Trends Food Sci Technol 2015. [DOI: 10.1016/j.tifs.2015.10.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
|
|
31
|
Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model. PLoS One 2015; 10:e0139416. [PMID: 26448624 PMCID: PMC4598156 DOI: 10.1371/journal.pone.0139416] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 09/14/2015] [Indexed: 12/21/2022] Open
Abstract
We have previously shown that mitochondria-targeted vitamin E (Mito-Vit-E), a mtROS specific antioxidant, improves cardiac performance and attenuates inflammation in a pneumonia-related sepsis model. In this study, we applied the same approaches to decipher the signaling pathway(s) of mtROS-dependent cardiac inflammation after sepsis. Sepsis was induced in Sprague Dawley rats by intratracheal injection of S. pneumoniae. Mito-Vit-E, vitamin E or vehicle was administered 30 minutes later. In myocardium 24 hours post-inoculation, Mito-Vit-E, but not vitamin E, significantly protected mtDNA integrity and decreased mtDNA damage. Mito-Vit-E alleviated sepsis-induced reduction in mitochondria-localized DNA repair enzymes including DNA polymerase γ, AP endonuclease, 8-oxoguanine glycosylase, and uracil-DNA glycosylase. Mito-Vit-E dramatically improved metabolism and membrane integrity in mitochondria, suppressed leakage of mtDNA into the cytoplasm, inhibited up-regulation of Toll-like receptor 9 (TLR9) pathway factors MYD88 and RAGE, and limited RAGE interaction with its ligand TFAM in septic hearts. Mito-Vit-E also deactivated NF-κB and caspase 1, reduced expression of the essential inflammasome component ASC, and decreased inflammatory cytokine IL–1β. In vitro, both Mito-Vit-E and TLR9 inhibitor OND-I suppressed LPS-induced up-regulation in MYD88, RAGE, ASC, active caspase 1, and IL–1β in cardiomyocytes. Since free mtDNA escaped from damaged mitochondria function as a type of DAMPs to stimulate inflammation through TLR9, these data together suggest that sepsis-induced cardiac inflammation is mediated, at least partially, through mtDNA-TLR9-RAGE. At last, Mito-Vit-E reduced the circulation of myocardial injury marker troponin-I, diminished apoptosis and amended morphology in septic hearts, suggesting that mitochondria-targeted antioxidants are a potential cardioprotective approach for sepsis.
Collapse
|
|
32
|
Brunst KJ, Baccarelli AA, Wright RJ. Integrating mitochondriomics in children's environmental health. J Appl Toxicol 2015; 35:976-91. [PMID: 26046650 PMCID: PMC4714560 DOI: 10.1002/jat.3182] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 04/23/2015] [Indexed: 12/18/2022]
Abstract
The amount of scientific research linking environmental exposures and childhood health outcomes continues to grow; yet few studies have teased out the mechanisms involved in environmentally-induced diseases. Cells can respond to environmental stressors in many ways: inducing oxidative stress/inflammation, changes in energy production and epigenetic alterations. Mitochondria, tiny organelles that each retains their own DNA, are exquisitely sensitive to environmental insults and are thought to be central players in these pathways. While it is intuitive that mitochondria play an important role in disease processes, given that every cell of our body is dependent on energy metabolism, it is less clear how environmental exposures impact mitochondrial mechanisms that may lead to enhanced risk of disease. Many of the effects of the environment are initiated in utero and integrating mitochondriomics into children's environmental health studies is a critical priority. This review will highlight (i) the importance of exploring environmental mitochondriomics in children's environmental health, (ii) why environmental mitochondriomics is well suited to biomarker development in this context, and (iii) how molecular and epigenetic changes in mitochondria and mitochondrial DNA (mtDNA) may reflect exposures linked to childhood health outcomes.
Collapse
Affiliation(s)
- Kelly J. Brunst
- Kravis Children’s Hospital, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Andrea A. Baccarelli
- Department of Environmental Health, Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Harvard T. H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA
| | - Rosalind J. Wright
- Kravis Children’s Hospital, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1428 Madison Avenue, New York, NY 10029, USA
| |
Collapse
|
|
33
|
Errichiello E, Balsamo A, Cerni M, Venesio T. Mitochondrial variants in MT-CO2 and D-loop instability are involved in MUTYH-associated polyposis. J Mol Med (Berl) 2015; 93:1271-81. [PMID: 26138249 DOI: 10.1007/s00109-015-1312-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 05/28/2015] [Accepted: 06/16/2015] [Indexed: 12/21/2022]
Abstract
UNLABELLED Mitochondrial DNA alterations have been widely reported in different human tumours, including colorectal carcinoma, but their mutational spectrum and pathogenic role in specific subsets of patients with polyposis syndromes have been poorly investigated. We compared the breadth of somatic variants across the mitochondrial genome of MUTYH-associated polyposis (MAP) patients with homogeneous groups of classical/attenuated familial adenomatous polyposis (FAP/AFAP) and sporadic cases. Overall, we screened 121 adenomas and seven adenocarcinomas and their corresponding germinal controls, for mitochondrial genes with a crucial role in oxidative phosphorylation and translation (MT-CO1, MT-CO2, MT-CO3, MT-TD, MT-TS1, MT-ATP6) as well as a hypervariable sequence (HV-II) within the control region displacement loop (D-loop), a marker of hypermutability and clonal expansion. The sequencing analysis revealed the presence of 17 variants, mostly causing non-synonymous changes in conserved amino acid residues, typically distributed in the MT-CO2 gene of MAP patients (P < 0.0001), who frequently carried the hot spot m.7763G>A variant. Accordingly, D-loop instability was also significantly associated with variants grouped inside the MT-CO2 gene (P = 0.0061). This is the first report showing a locus-specific distribution of mitochondrial DNA alterations in a subtype of colorectal tumourigenesis. In addition, our findings suggest that MT-CO2 variants, representing early molecular events in MAP tumorigenesis, might be a potential prognostic biomarker for the cancer-risk assessment of patients affected by this syndrome. KEY MESSAGES We compared the frequencies of mtDNA variants in MAP vs. FAP/AFAP/sporadic patients. We found a gene-specific (MT-CO2) distribution of mtDNA variants in MAP cases. Most mtDNA variants caused non-synonymous changes in conserved amino acid residues. D-loop instability was significantly associated with variants grouped inside MT-CO2. MT-CO2 variants might be a potential prognostic biomarker in MAP patients.
Collapse
Affiliation(s)
- Edoardo Errichiello
- Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy
| | - Antonella Balsamo
- Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy
| | - Marianna Cerni
- Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy
| | - Tiziana Venesio
- Molecular Pathology Laboratory, Unit of Pathology, Institute for Cancer Research and Treatment, FPO-IRCCS, Strada Provinciale 142, 10060, Candiolo, Torino, Italy.
| |
Collapse
|
|
34
|
Pouget JP, Lozza C, Deshayes E, Boudousq V, Navarro-Teulon I. Introduction to radiobiology of targeted radionuclide therapy. Front Med (Lausanne) 2015; 2:12. [PMID: 25853132 PMCID: PMC4362338 DOI: 10.3389/fmed.2015.00012] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 02/25/2015] [Indexed: 12/21/2022] Open
Abstract
During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRTs) are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT) and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors, which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure, and low absorbed dose rate) differ from those of conventional EBRT (homogeneous irradiation, short exposure, and high absorbed dose rate), and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose-effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related) and non-targeted effects (assumed to be non-dose-related) of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main challenges of TRT in the future.
Collapse
Affiliation(s)
- Jean-Pierre Pouget
- Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
- INSERM, U1194, Montpellier, France
- Université de Montpellier, Montpellier, France
- Institut régional du Cancer de Montpellier, Montpellier, France
| | - Catherine Lozza
- Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
- INSERM, U1194, Montpellier, France
- Université de Montpellier, Montpellier, France
- Institut régional du Cancer de Montpellier, Montpellier, France
| | - Emmanuel Deshayes
- Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
- INSERM, U1194, Montpellier, France
- Université de Montpellier, Montpellier, France
- Institut régional du Cancer de Montpellier, Montpellier, France
| | - Vincent Boudousq
- Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
- INSERM, U1194, Montpellier, France
- Université de Montpellier, Montpellier, France
- Institut régional du Cancer de Montpellier, Montpellier, France
| | - Isabelle Navarro-Teulon
- Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
- INSERM, U1194, Montpellier, France
- Université de Montpellier, Montpellier, France
- Institut régional du Cancer de Montpellier, Montpellier, France
| |
Collapse
|
|
35
|
Hu D, Wu CQ, Li ZJ, Liu Y, Fan X, Wang QJ, Ding RG. Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria. Toxicol Appl Pharmacol 2015; 284:134-41. [PMID: 25727309 DOI: 10.1016/j.taap.2015.02.018] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 01/28/2015] [Accepted: 02/17/2015] [Indexed: 01/14/2023]
Abstract
OBJECTIVE To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. METHODS Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50μM) for 48h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrial respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p<0.05. RESULTS Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. CONCLUSION All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles.
Collapse
Affiliation(s)
- Dan Hu
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China
| | - Chun-qi Wu
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China
| | - Ze-jun Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China; Guang Dong Pharmaceutical University, Guangzhou 510006, PR China
| | - Yue Liu
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China
| | - Xing Fan
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China
| | - Quan-jun Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China.
| | - Ri-gao Ding
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China.
| |
Collapse
|
|
36
|
Alternative solutions and new scenarios for translesion DNA synthesis by human PrimPol. DNA Repair (Amst) 2015; 29:127-38. [PMID: 25746449 DOI: 10.1016/j.dnarep.2015.02.013] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 02/12/2015] [Accepted: 02/13/2015] [Indexed: 12/29/2022]
Abstract
PrimPol is a recently described DNA polymerase that has the virtue of initiating DNA synthesis. In addition of being a sensu stricto DNA primase, PrimPol's polymerase activity has a large capacity to tolerate different kind of lesions. The different strategies used by PrimPol for DNA damage tolerance are based on its capacity to "read" certain lesions, to skip unreadable lesions, and as an ultimate solution, to restart DNA synthesis beyond the lesion thus acting as a TLS primase. This lesion bypass potential, revised in this article, is strengthened by the preferential use of moderate concentrations of manganese ions as the preferred metal activator. We show here that PrimPol is able to extend RNA primers with ribonucleotides, even when bypassing 8oxoG lesions, suggesting a potential new scenario for PrimPol as a TLS polymerase assisting transcription. We also show that PrimPol displays a high degree of versatility to accept or induce distortions of both primer and template strands, creating alternative alignments based on microhomology that would serve to skip unreadable lesions and to connect separate strands. In good agreement, PrimPol is highly prone to generate indels at short nucleotide repeats. Finally, an evolutionary view of the relationship between translesion synthesis and primase functions is briefly discussed.
Collapse
|
|
37
|
Zidovudine induces downregulation of mitochondrial deoxynucleoside kinases: implications for mitochondrial toxicity of antiviral nucleoside analogs. Antimicrob Agents Chemother 2014; 58:6758-66. [PMID: 25182642 DOI: 10.1128/aac.03613-14] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial phosphorylation of deoxynucleosides in the synthesis of the DNA precursors required for mitochondrial DNA (mtDNA) replication and are essential for mitochondrial function. Antiviral nucleosides are known to cause toxic mitochondrial side effects. Here, we examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT) (zidovudine) on mitochondrial TK2 and dGK levels and found that AZT treatment led to downregulation of mitochondrial TK2 and dGK in U2OS cells, whereas cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) levels were not affected. The AZT effects on mitochondrial TK2 and dGK were similar to those of oxidants (e.g., hydrogen peroxide); therefore, we examined the oxidative effects of AZT. We found a modest increase in cellular reactive oxygen species (ROS) levels in the AZT-treated cells. The addition of uridine to AZT-treated cells reduced ROS levels and protein oxidation and prevented the degradation of mitochondrial TK2 and dGK. In organello studies indicated that the degradation of mitochondrial TK2 and dGK is a mitochondrial event. These results suggest that downregulation of mitochondrial TK2 and dGK may lead to decreased mitochondrial DNA precursor pools and eventually mtDNA depletion, which has significant implications for the regulation of mitochondrial nucleotide biosynthesis and for antiviral therapy using nucleoside analogs.
Collapse
|
|
38
|
Molteni CG, Principi N, Esposito S. Reactive oxygen and nitrogen species during viral infections. Free Radic Res 2014; 48:1163-9. [PMID: 25039433 DOI: 10.3109/10715762.2014.945443] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Oxygen and nitrogen radicals are frequently produced during viral infections. These radicals are not only a physiological mechanism for pathogen clearance but also result in many pathological consequences. Low concentrations of radicals can promote viral replication; however, high concentrations of radicals can also inhibit viral replication and are detrimental to the cell due to their mitogenic activity. We reviewed the detailed mechanisms behind oxygen and nitrogen radical production and focused on how viruses induce radical production. In addition, we examined the effects of oxygen and nitrogen radicals on both the virus and host. We also reviewed enzymatic and chemical detoxification mechanisms and recent advances in therapeutic antioxidant applications. Many molecules that modulate the redox balance have yielded promising results in cell and animal models of infection. This encourages their use in clinical practice either alone or with existing therapies. However, since the redox balance also plays an important role in host defence against pathogens, carefully designed clinical trials are needed to assess the therapeutic benefits and secondary effects of these molecules and whether these effects differ between different types of viral infections.
Collapse
Affiliation(s)
- C G Molteni
- Department of Pathophysiology and Transplantation, Pediatric Highly Intensive Care Unit, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
| | | | | |
Collapse
|
|
39
|
Chen R, Lin J, Hong J, Han D, Zhang AD, Lan R, Fu L, Wu Z, Lin J, Zhang W, Wang Z, Chen W, Chen C, Zhang H. Potential toxicity of quercetin: The repression of mitochondrial copy number via decreased POLG expression and excessive TFAM expression in irradiated murine bone marrow. Toxicol Rep 2014; 1:450-458. [PMID: 28962259 PMCID: PMC5598249 DOI: 10.1016/j.toxrep.2014.07.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/22/2014] [Accepted: 07/22/2014] [Indexed: 11/21/2022] Open
Abstract
The cytotoxicity of quercetin is not well understood. Using an ICR murine model, we unexpectedly found that mice exposed to 7 Gy total body irradiation (TBI) exhibited general in vivo toxicity after receiving quercetin (100 mg/kg PO), whereas this result was not observed in mice that received TBI only. In order to understand the involvement of alterations in mitochondrial biogenesis, we used a real-time qPCR to analyze the mitochondrial DNA copy number (mtDNAcn) by amplifying the MTRNR1 (12S rRNA) gene in murine bone marrow. We also utilized reverse transcription qPCR to determine the mRNA amounts transcribed from the polymerase gamma (POLG), POLG2, and mammalian mitochondrial transcription factor A (TFAM) genes in the tissue. In the mice exposed to TBI combined with quercetin, we found: (1) the radiation-induced increase of mtDNAcn was inhibited with a concurrent significant decrease in POLG expression; (2) TFAM expression was significantly increased; and (3) the expression of POLG2 was not influenced by the treatments. These data suggest that the overall toxicity was in part associated with the decrease in mtDNAcn, an effect apparently caused by the inhibition of POLG expression and overexpression of TFAM; unaltered POLG2 expression did not seem to contribute to toxicity.
Collapse
Affiliation(s)
- Ruiqing Chen
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Jingan Lin
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Jingshen Hong
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Deping Han
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Addison D Zhang
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Ruilong Lan
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Lengxi Fu
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Zhaoyang Wu
- Department of Orthopedics, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Jianhua Lin
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Weijian Zhang
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Zeng Wang
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Wei Chen
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Chun Chen
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Hengshan Zhang
- Central Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| |
Collapse
|
|
40
|
Chang CC, Jou SH, Lin TT, Liu CS. Mitochondrial DNA variation and increased oxidative damage in euthymic patients with bipolar disorder. Psychiatry Clin Neurosci 2014; 68:551-7. [PMID: 24447331 DOI: 10.1111/pcn.12163] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 01/03/2014] [Accepted: 01/15/2014] [Indexed: 12/13/2022]
Abstract
AIM The aim of this study was to compare alterations of mitochondrial DNA (mtDNA) copy number, single nucleotide polymorphisms, and oxidative damage of mtDNA in clinically stable patients with bipolar I disorder (BD). METHODS Patients meeting DSM-IV diagnostic criteria for BD were recruited from the psychiatric outpatient clinic at Changhua Christian Hospital, Taiwan. They were clinically stable and their medications had not changed for at least the preceding 2 months. Exclusion criteria were substance-induced psychotic disorder, eating disorder, anxiety disorder or illicit substance abuse. Comparison subjects did not have any history of major psychiatric disorders and they were non-smokers. By analyzing peripheral blood leukocytes, copy number, single nucleotide polymorphisms and oxidative damage of mtDNA were compared between the two groups. RESULTS The median age of the subjects was 38 years and 41.5 years in the comparison and BD groups, respectively. The leukocyte mtDNA copy number of the BD group was significantly lower than that of the comparison group (P < 0.001). BD patients had significantly higher mitochondrial oxidative damage than the comparison group (6.1 vs 3.9, P < 0.001). After generalized linear model adjusting with age, sex, smoking, family history, and psychotropic use, mtDNA copy number was still significantly lower in the BD group (P < 0.001). MtDNA oxidative damage was positively correlated with age (P = 0.034), although mtDNA oxidative damage was similar between these two groups. CONCLUSION Possible involvement of oxidative stress and mitochondria in the pathophysiology of BD needs more large-scale studies. It is important that psychiatrists retain a high level of suspicion for mitochondrial dysfunction in patients with bipolar disorder.
Collapse
Affiliation(s)
- Cheng-Chen Chang
- Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan; The Institute of Medicine, Chungshan Medical University, Taichung, Taiwan
| | | | | | | |
Collapse
|
|
41
|
Ravi S, Mitchell T, Kramer P, Chacko B, Darley-Usmar VM. Mitochondria in monocytes and macrophages-implications for translational and basic research. Int J Biochem Cell Biol 2014; 53:202-207. [PMID: 24863362 DOI: 10.1016/j.biocel.2014.05.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 05/13/2014] [Accepted: 05/15/2014] [Indexed: 12/14/2022]
Abstract
The mitochondrion plays a crucial role in the immune system particularly in regulating the responses of monocytes and macrophages to tissue injury, pathogens, and inflammation. In systemic diseases such as atherosclerosis and chronic kidney disease (CKD), it has been established that disruption of monocyte and macrophage function can lead to chronic inflammation. Polarization of macrophages into the pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes results in distinct metabolic reprograming which corresponds to the progression and resolution of inflammation. In this review, we will discuss the role of the mitochondrion in monocyte and macrophage function and how these cells specifically influence the pathophysiology of atherosclerosis and CKD. We propose that assessing monocyte bioenergetics in different disease states could (1) enhance our understanding of the energetic perturbations occurring in systemic inflammatory conditions and (2) aid in identifying therapeutic interventions to mitigate these disorders in patients.
Collapse
Affiliation(s)
- Saranya Ravi
- Department of Pathology, UAB Mitochondrial Medicine Laboratory, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Tanecia Mitchell
- Department of Pathology, UAB Mitochondrial Medicine Laboratory, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Philip Kramer
- Department of Pathology, UAB Mitochondrial Medicine Laboratory, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Balu Chacko
- Department of Pathology, UAB Mitochondrial Medicine Laboratory, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Victor M Darley-Usmar
- Department of Pathology, UAB Mitochondrial Medicine Laboratory, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| |
Collapse
|
|
42
|
Lee HC, Huang KH, Yeh TS, Chi CW. Somatic alterations in mitochondrial DNA and mitochondrial dysfunction in gastric cancer progression. World J Gastroenterol 2014; 20:3950-3959. [PMID: 24744584 PMCID: PMC3983450 DOI: 10.3748/wjg.v20.i14.3950] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 12/26/2013] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
Energy metabolism reprogramming was recently identified as one of the cancer hallmarks. One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA (mtDNA). In the past decades, several types of somatic mtDNA alterations have been identified in gastric cancer. However, the role of these mtDNA alterations in gastric cancer progression remains unclear. In this review, we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer. The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed. We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers. The two primary mutation types (transition mutations and mononucleotide or dinucleotide repeat instability) imply potential causative factors. Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer. The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies.
Collapse
|
|
43
|
Li M, Gonon G, Buonanno M, Autsavapromporn N, de Toledo SM, Pain D, Azzam EI. Health risks of space exploration: targeted and nontargeted oxidative injury by high-charge and high-energy particles. Antioxid Redox Signal 2014; 20:1501-23. [PMID: 24111926 PMCID: PMC3936510 DOI: 10.1089/ars.2013.5649] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
SIGNIFICANCE During deep space travel, astronauts are often exposed to high atomic number (Z) and high-energy (E) (high charge and high energy [HZE]) particles. On interaction with cells, these particles cause severe oxidative injury and result in unique biological responses. When cell populations are exposed to low fluences of HZE particles, a significant fraction of the cells are not traversed by a primary radiation track, and yet, oxidative stress induced in the targeted cells may spread to nearby bystander cells. The long-term effects are more complex because the oxidative effects persist in progeny of the targeted and affected bystander cells, which promote genomic instability and may increase the risk of age-related cancer and degenerative diseases. RECENT ADVANCES Greater understanding of the spatial and temporal features of reactive oxygen species bursts along the tracks of HZE particles, and the availability of facilities that can simulate exposure to space radiations have supported the characterization of oxidative stress from targeted and nontargeted effects. CRITICAL ISSUES The significance of secondary radiations generated from the interaction of the primary HZE particles with biological material and the mitigating effects of antioxidants on various cellular injuries are central to understanding nontargeted effects and alleviating tissue injury. FUTURE DIRECTIONS Elucidation of the mechanisms underlying the cellular responses to HZE particles, particularly under reduced gravity and situations of exposure to additional radiations, such as protons, should be useful in reducing the uncertainty associated with current models for predicting long-term health risks of space radiation. These studies are also relevant to hadron therapy of cancer.
Collapse
Affiliation(s)
- Min Li
- 1 Department of Radiology, Cancer Center, Rutgers University-New Jersey Medical School , Newark, New Jersey
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Havaki S, Kotsinas A, Chronopoulos E, Kletsas D, Georgakilas A, Gorgoulis VG. The role of oxidative DNA damage in radiation induced bystander effect. Cancer Lett 2014; 356:43-51. [PMID: 24530228 DOI: 10.1016/j.canlet.2014.01.023] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 12/08/2013] [Accepted: 01/24/2014] [Indexed: 02/06/2023]
Abstract
Ionizing radiation (IR) has been described as a double-edged sword, since it is used for diagnostic and therapeutic medical applications, and at the same time it is a well known human mutagen and carcinogen, causing wide-ranging chromosomal aberrations. It is nowadays accepted that the detrimental effects of IR are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects. This review presents the role of oxidative stress in the induction of bystander effects referring to the types of the implicated oxidative DNA lesions, the contributing intercellular and intracellular stress mediators, the way they are transmitted from irradiated to bystander cells and finally, the complex role of the bystander effect in the therapeutic efficacy of radiation treatment of cancer.
Collapse
Affiliation(s)
- Sophia Havaki
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece
| | - Athanassios Kotsinas
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece
| | | | - Dimitris Kletsas
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Center for Scientific Research Demokritos, Athens, Greece
| | - Alexandros Georgakilas
- Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780 Athens, Greece
| | - Vassilis G Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece; Biomedical Research Foundation, Academy of Athens, Athens, Greece; Faculty Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, M13 9WL, UK.
| |
Collapse
|
|
45
|
Pathogenesis of chronic cardiorenal syndrome: is there a role for oxidative stress? Int J Mol Sci 2013; 14:23011-32. [PMID: 24264044 PMCID: PMC3856103 DOI: 10.3390/ijms141123011] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Revised: 10/30/2013] [Accepted: 11/01/2013] [Indexed: 02/07/2023] Open
Abstract
Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental studies have identified several dysregulated pathways in heart failure and in chronic kidney disease that lead to increased oxidative stress. A decrease in mitochondrial oxidative metabolism has been reported in cardiomyocytes during heart failure. This is balanced by a compensatory increase in glucose uptake and glycolysis with consequent decrease in myocardial ATP content. In the kidneys, both NADPH oxidase and mitochondrial metabolism are important sources of TGF-β1-induced cellular ROS. NOX-dependent oxidative activation of transcription factors such as NF-kB and c-jun leads to increased expression of renal target genes (phospholipaseA2, MCP-1 and CSF-1, COX-2), thus contributing to renal interstitial fibrosis and inflammation. In the present article, we postulate that, besides contributing to both cardiac and renal dysfunction, increased oxidative stress may also play a crucial role in cardiorenal syndrome development and progression. In particular, an imbalance between the renin-angiotensin-aldosterone system, the sympathetic nervous system, and inflammation may favour cardiorenal syndrome through an excessive oxidative stress production. This article also discusses novel therapeutic strategies for their potential use in the treatment of patients affected by cardiorenal syndrome.
Collapse
|
|
46
|
Holley AK, Dhar SK, St Clair DK. Curbing cancer's sweet tooth: is there a role for MnSOD in regulation of the Warburg effect? Mitochondrion 2013; 13:170-88. [PMID: 22820117 PMCID: PMC4604438 DOI: 10.1016/j.mito.2012.07.104] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Revised: 07/04/2012] [Accepted: 07/10/2012] [Indexed: 01/27/2023]
Abstract
Reactive oxygen species (ROS), while vital for normal cellular function, can have harmful effects on cells, leading to the development of diseases such as cancer. The Warburg effect, the shift from oxidative phosphorylation to glycolysis, even in the presence of adequate oxygen, is an important metabolic change that confers many growth and survival advantages to cancer cells. Reactive oxygen species are important regulators of the Warburg effect. The mitochondria-localized antioxidant enzyme manganese superoxide dismutase (MnSOD) is vital to survival in our oxygen-rich atmosphere because it scavenges mitochondrial ROS. MnSOD is important in cancer development and progression. However, the significance of MnSOD in the regulation of the Warburg effect is just now being revealed, and it may significantly impact the treatment of cancer in the future.
Collapse
Affiliation(s)
- Aaron K. Holley
- Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536
| | - Sanjit Kumar Dhar
- Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536
| | - Daret K. St Clair
- Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536
| |
Collapse
|
|
47
|
Verdejo HE, del Campo A, Troncoso R, Gutierrez T, Toro B, Quiroga C, Pedrozo Z, Munoz JP, Garcia L, Castro PF, Lavandero S. Mitochondria, myocardial remodeling, and cardiovascular disease. Curr Hypertens Rep 2013; 14:532-9. [PMID: 22972531 DOI: 10.1007/s11906-012-0305-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease.
Collapse
Affiliation(s)
- Hugo E Verdejo
- Centro Estudios Moleculares de la Célula, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Analysis of mitochondrial gene expression. Methods Mol Biol 2013. [PMID: 23494316 DOI: 10.1007/978-1-62703-302-2_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
Dictyostelium provides a well-established model system for the study of mitochondrial biology and disease. A complete mitochondrial transcription and RNA-processing map has been generated, while the start site for transcription and the responsible RNA polymerase have also been identified, as have the major cotranscriptional cleavage sites that generate the mature mitochondrial RNA molecules. Here we describe the methods deployed to study mitochondrial gene transcription and RNA processing in Dictyostelium.
Collapse
|
|
49
|
Yu M, Wan Y, Zou Q. Somatic mitochondrial DNA mutations in Chinese patients with osteosarcoma. Int J Exp Pathol 2013; 94:126-32. [PMID: 23441585 DOI: 10.1111/iep.12015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 12/15/2012] [Indexed: 12/13/2022] Open
Abstract
Somatic mutations in mitochondrial DNA (mtDNA) have been long proposed to drive the pathogenesis and progression of human malignancies. Previous investigations have revealed a high frequency of somatic mutations in the D-loop control region of mtDNA in osteosarcoma. However, little is known with regard to whether or not somatic mutations also occur in the coding regions of mtDNA in osteosarcoma. To test this possibility, in the present study we screened somatic mutations over the full-length mitochondrial genome of 31 osteosarcoma tumour tissue samples, and corresponding peripheral blood samples from the same cohort of patients. We detected a sum of 11 somatic mutations in the mtDNA coding regions in our series. Nine of them were missense or frameshift mutations that have the potential to hamper mitochondrial respiratory function. In combination with our earlier observations on the D-loop fragment, 71.0% (22/31) of patients with osteosarcoma carried at least one somatic mtDNA mutation, and a total of 40 somatic mutations were identified. Amongst them, 29 (72.5%) were located in the D-loop region, two (5%) were in the sequences of the tRNA genes, two (5%) were in the mitochondrial ATP synthase subunit 6 gene and seven (17.5%) occurred in genes encoding components of the mitochondrial respiratory complexes. In addition, somatic mtDNA mutation was not closely associated with the clinicopathological characteristics of osteosarcoma. Together, these findings suggest that somatic mutations are highly prevalent events in both coding and non-coding regions of mtDNA in osteosarcoma. Some missense and frameshift mutations are putatively harmful to proper mitochondrial activity and might play vital roles in osteosarcoma carcinogenesis.
Collapse
Affiliation(s)
- Man Yu
- Ontario Cancer Institute/Princess Margaret Hospital, University Health Network and University of Toronto, Toronto, ON, Canada
| | | | | |
Collapse
|
|
50
|
Yu M, Wan Y, Zou Q. Somatic mutations of the mitochondrial genome in Chinese patients with Ewing sarcoma. Hum Pathol 2013; 44:1350-6. [PMID: 23375644 DOI: 10.1016/j.humpath.2012.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Revised: 11/09/2012] [Accepted: 11/13/2012] [Indexed: 12/16/2022]
Abstract
Somatic mutations in mitochondrial DNA (mtDNA) have been long proposed to drive initiation and progression of human malignancies. Our previous study revealed a high prevalence of somatic mutations in the D-loop region of mtDNA in Ewing sarcoma (EWS). However, it is unclear whether somatic mutations also occur in the coding regions of mtDNA in EWS. To test this possibility, in the present study, we sequenced the whole mitochondrial genome from 20 cases of EWS specimens and their corresponding peripheral blood samples. We identified a total of 6 somatic mutations in the mtDNA coding regions in our EWS series, and 5 of them were missense or frame-shift mutations that have the potential to directly influence proper mitochondrial function. In combination with our earlier observations on the D-loop fragment, 70% (14/20) of EWS tissues appeared to harbor somatic mtDNA mutations. Among the identified 25 somatic mutations, 19 (76%) were located in the D-loop control region, 1 (4%) was in the sequence of the tRNA(Val) gene, 1 (4%) was in the mitochondrial ATP synthase subunit 6 gene, and 4 (16%) occurred in genes encoding components of the mitochondrial respiratory complexes. In addition, patients carrying somatic mtDNA mutations did not show significant association with their clinicopathologic characteristics. Together, these findings suggest that somatic mtDNA mutations occur in both protein coding and noncoding regions of mtDNA, which may play critical roles in the pathogenesis of EWS and should be further explored for its possible use as a novel marker for monitoring EWS occurrence and advancement.
Collapse
Affiliation(s)
- Man Yu
- Ontario Cancer Institute/Princess Margaret Hospital, University Health Network and University of Toronto, Toronto, M5G 2M9 Ontario, Canada.
| | | | | |
Collapse
|