18
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Differential Expression of Complement Markers in Normal and AMD Transmitochondrial Cybrids

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Purpose

          Variations in mitochondrial DNA (mtDNA) and abnormalities in the complement pathways have been implicated in the pathogenesis of age-related macular degeneration (AMD). This study was designed to determine the effects of mtDNA from AMD subjects on the complement pathway.

          Methods

          Transmitochondrial cybrids were prepared by fusing platelets from AMD and age-matched Normal subjects with Rho 0 (lacking mtDNA) human ARPE-19 cells. Quantitative PCR and Western blotting were performed to examine gene and protein expression profiles, respectively, of complement markers in these cybrids. Bioenergetic profiles of Normal and AMD cybrids were examined using the Seahorse XF24 flux analyzer.

          Results

          Significant decreases in the gene and protein expression of complement inhibitors, along with significantly higher levels of complement activators, were found in AMD cybrids compared to Older-Normal cybrids. Seahorse flux data demonstrated that the bioenergetic profiles for Older-Normal and Older-AMD cybrid samples were similar to each other but were lower compared to Young-Normal cybrid samples.

          Conclusion

          In summary, since all cybrids had identical nuclei and differed only in mtDNA content, the observed changes in components of complement pathways can be attributed to mtDNA variations in the AMD subjects, suggesting that mitochondrial genome and retrograde signaling play critical roles in this disease. Furthermore, the similar bioenergetic profiles of AMD and Older-Normal cybrids indicate that the signaling between mitochondria and nuclei are probably not via a respiratory pathway.

          Related collections

          Most cited references55

          • Record: found
          • Abstract: found
          • Article: not found

          Prevalence of age-related macular degeneration in the United States.

          To estimate the prevalence and distribution of age-related macular degeneration (AMD) in the United States by age, race/ethnicity, and gender. Summary prevalence estimates of drusen 125 microm or larger, neovascular AMD, and geographic atrophy were prepared separately for black and white persons in 5-year age intervals starting at 40 years. The estimated rates were based on a meta-analysis of recent population-based studies in the United States, Australia, and Europe. These rates were applied to 2000 US Census data and to projected US population figures for 2020 to estimate the number of the US population with drusen and AMD. The overall prevalence of neovascular AMD and/or geographic atrophy in the US population 40 years and older is estimated to be 1.47% (95% confidence interval, 1.38%-1.55%), with 1.75 million citizens having AMD. The prevalence of AMD increased dramatically with age, with more than 15% of the white women older than 80 years having neovascular AMD and/or geographic atrophy. More than 7 million individuals had drusen measuring 125 microm or larger and were, therefore, at substantial risk of developing AMD. Owing to the rapidly aging population, the number of persons having AMD will increase by 50% to 2.95 million in 2020. Age-related macular degeneration was far more prevalent among white than among black persons. Age-related macular degeneration affects more than 1.75 million individuals in the United States. Owing to the rapid aging of the US population, this number will increase to almost 3 million by 2020.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mitochondrial retrograde signaling.

            Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus under normal and pathophysiological conditions. The best understood of such pathways is retrograde signaling in the budding yeast Saccharomyces cerevisiae. It involves multiple factors that sense and transmit mitochondrial signals to effect changes in nuclear gene expression; these changes lead to a reconfiguration of metabolism to accommodate cells to defects in mitochondria. Analysis of regulatory factors has provided us with a mechanistic view of regulation of retrograde signaling. Here we review advances in the yeast retrograde signaling pathway and highlight its regulatory factors and regulatory mechanisms, its physiological functions, and its connection to nutrient sensing, TOR signaling, and aging.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The role of complement in inflammatory diseases from behind the scenes into the spotlight.

              Our understanding of the biology of the complement system has undergone a drastic metamorphosis since its original discovery. This system, which was traditionally primarily described as a "complement" to humoral immunity, is now perceived as a central constituent of innate immunity, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement is an assembly of proteins found in the blood and body fluids and on cell surfaces. Soluble complement components form the proteolytic cascade, whose activation leads to the generation of complement effectors that target various cells involved in the immune response. Membrane-bound receptors and regulators transmit signals from complement effectors to target cells and limit complement activation to the surfaces of pathogens and damaged or activated host cells. The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this "defense machinery" contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 August 2016
                2016
                : 11
                : 8
                : e0159828
                Affiliations
                [1 ]Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States of America
                [2 ]College of Osteopathic Medicine, Touro University Nevada, Nevada, United States of America
                [3 ]VA Medical Center Long Beach Hospital, Long Beach, California, United States of America
                [4 ]Cedars-Sinai Medical Center, Los Angeles, California, United States of America
                [5 ]Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, United States of America
                University of Florida, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: SN MCK MC.

                • Performed the experiments: SN MC MK KT.

                • Analyzed the data: SN MCK MC.

                • Contributed reagents/materials/analysis tools: MCK BDK AN SL.

                • Wrote the paper: SN MCK.

                Article
                PONE-D-15-53334
                10.1371/journal.pone.0159828
                4972370
                27486856
                0d9835cb-e796-4d1f-97e9-a9e7b816af52
                © 2016 Nashine et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 December 2015
                : 9 July 2016
                Page count
                Figures: 3, Tables: 6, Pages: 20
                Funding
                Funded by: Arnold and Mabel Beckman Foundation Postdoctoral Fellowship
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100002806, Discovery Eye Foundation;
                Funded by: funder-id http://dx.doi.org/10.13039/100008226, Arnold and Mabel Beckman Initiative for Macular Research;
                Funded by: Guenther Foundation
                Funded by: Polly and Michael Smith Foundation
                Funded by: Max Factor Family Foundation
                Funded by: Cantor Foundation, Iris & B. Gerald
                This work was supported by the Arnold and Mabel Beckman Foundation, Discovery Eye Foundation, Guenther Foundation, Beckman Initiative for Macular Research, Polly and Michael Smith Foundation, Max Factor Family Foundation, Iris and B. Gerald Cantor Foundation and SRN is a Arnold and Mabel Beckman Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Complement System
                Complement Activation
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Complement System
                Complement Activation
                Biology and Life Sciences
                Immunology
                Immune System
                Complement System
                Complement Activation
                Medicine and Health Sciences
                Immunology
                Immune System
                Complement System
                Complement Activation
                Biology and Life Sciences
                Immunology
                Immune System Proteins
                Complement System
                Complement Activation
                Medicine and Health Sciences
                Immunology
                Immune System Proteins
                Complement System
                Complement Activation
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Complement System
                Complement Activation
                Biology and Life Sciences
                Biochemistry
                Bioenergetics
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Energy-Producing Organelles
                Mitochondria
                Biology and life sciences
                Genetics
                DNA
                Forms of DNA
                Mitochondrial DNA
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                Forms of DNA
                Mitochondrial DNA
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Complement System
                Complement Inhibitors
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Complement System
                Complement Inhibitors
                Biology and Life Sciences
                Immunology
                Immune System
                Complement System
                Complement Inhibitors
                Medicine and Health Sciences
                Immunology
                Immune System
                Complement System
                Complement Inhibitors
                Biology and Life Sciences
                Immunology
                Immune System Proteins
                Complement System
                Complement Inhibitors
                Medicine and Health Sciences
                Immunology
                Immune System Proteins
                Complement System
                Complement Inhibitors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Complement System
                Complement Inhibitors
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Complement System
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Complement System
                Biology and Life Sciences
                Immunology
                Immune System
                Complement System
                Medicine and Health Sciences
                Immunology
                Immune System
                Complement System
                Biology and Life Sciences
                Immunology
                Immune System Proteins
                Complement System
                Medicine and Health Sciences
                Immunology
                Immune System Proteins
                Complement System
                Biology and Life Sciences
                Biochemistry
                Proteins
                Immune System Proteins
                Complement System
                Medicine and Health Sciences
                Geriatrics
                Geriatric Ophthalmology
                Macular Degeneration
                Medicine and Health Sciences
                Ophthalmology
                Geriatric Ophthalmology
                Macular Degeneration
                Medicine and Health Sciences
                Ophthalmology
                Retinal Disorders
                Macular Disorders
                Macular Degeneration
                Medicine and Health Sciences
                Ophthalmology
                Retinal Disorders
                Retinal Degeneration
                Macular Degeneration
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
                Haplogroups
                Biology and Life Sciences
                Genetics
                Population Genetics
                Haplogroups
                Biology and Life Sciences
                Population Biology
                Population Genetics
                Haplogroups
                Biology and Life Sciences
                Biochemistry
                Bioenergetics
                Custom metadata
                All relevant data are within the paper.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article