Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

Oxidative Medicine and Cellular Longevity, Aug 2015

Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson’s and Huntington’s disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

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Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics Levente Szalárdy,1 Dénes Zádori,1 Péter Klivényi,1 József Toldi,2,3 and László Vécsei1,3 1Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged 6725, Hungary 2Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép Fasor 52, Szeged 6726, Hungary 3MTA-SZTE Neuroscience Research Group, Semmelweis u. 6, Szeged 6725, Hungary Received 6 March 2015; Accepted 15 April 2015 Academic Editor: José Pedraza-Chaverri Copyright © 2015 Levente Szalárdy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson’s and Huntington’s disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes. 1. The Man Amused by the Dance of Electrons “The fuel of life is electron, or more exactly, the energy it takes over from photons in photosynthesis, and gives up gradually while flowing through the cellular machinery.” This imagination originates from Professor Albert Szent-Györgyi, a Hungarian physician and biochemist, former chair of the Department of Medical Chemistry and the Department of Organic Chemistry at the University of Szeged from 1930 and 1935, respectively, until the end of World War II in 1945. His early research activities in Groningen and later in Cambridge conducted on biological combustion, cellular respiration, and energy production of plants lead to the discovery of a reducing substance called “hexuronic acid,” a substance that is able to lose and regain hydrogen atoms and capable of protecting plants from “browning,” an injury that he characterized as oxidative damage due to the excessive activity of an enzyme, peroxidase. This “antioxidant” substance was later proved by Szent-Györgyi to be equivalent with a potent antiscorbutic (antiscurvy) agent and was given the name ascorbic acid, currently widely known as vitamin C, which is most abundant in citrus fruits and paprika, an emblematic vegetable of Szeged. At this time, performing ongoing research in the field of biological respiration, Szent-Györgyi discovered and identified the catalysis of fumaric acid among other steps of the tricarboxylic acid cycle (also referred to as Szent-Györgyi–Krebs cycle, citric acid cycle), an essential component of cellular respiration that provides reducing equivalents for terminal oxidation and thereby energy production from metabolic products of dietary macromolecules. “For his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid,” Albert Szent-Györgyi was awarded Nobel Prize in Physiology or Medicine in 1937. In addition to his pioneering work in muscle research—including the discovery of actin and myosin proteins and the mechanism of their joint function—as well as the discovery of vitamin P (flavanone), his subsequent research interests focused on the interactions of proteins and free radicals and their role in regulating cell division and cancer development, and he published a number of books and papers about his findings and scientific theories of bioenergetics and bioelectronics and their roles in health and disease. Following the imaginations of our honored predecessor, this paper reviews the concepts on the role of impairments in m (...truncated)


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Levente Szalárdy, Dénes Zádori, Péter Klivényi, József Toldi, László Vécsei. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics, Oxidative Medicine and Cellular Longevity, 2015, 2015, DOI: 10.1155/2015/498401