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

Szalárdy L, Zádori D, Klivényi P, Toldi J, Vécsei L - Oxid Med Cell Longev (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged 6725, Hungary.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the generation and the effects of free radicals within the mitochondria. The leakage of electrons from the mitochondrial ETC at complexes I and III results in the formation of superoxide anion. The high reactivity of this molecule evokes a harmful cascade mechanism including the formation of reactive oxygen and nitrogen species. The cascade mechanism deteriorates the functional groups of major components of all kinds of biomolecules (carbohydrates, lipids, proteins, and nucleic acids). In case of pronounced electron leakage or deficient antioxidant protection, a vicious circle of mitochondrial dysfunction develops.
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fig2: Schematic representation of the generation and the effects of free radicals within the mitochondria. The leakage of electrons from the mitochondrial ETC at complexes I and III results in the formation of superoxide anion. The high reactivity of this molecule evokes a harmful cascade mechanism including the formation of reactive oxygen and nitrogen species. The cascade mechanism deteriorates the functional groups of major components of all kinds of biomolecules (carbohydrates, lipids, proteins, and nucleic acids). In case of pronounced electron leakage or deficient antioxidant protection, a vicious circle of mitochondrial dysfunction develops.

Mentions: Free radicals are molecules possessing unpaired electrons in their outer orbit. This renders them highly reactive towards organic macromolecules such as carbohydrates, nucleic acids, proteins, and lipids, which suffer “injury” during such a reaction. The main routes of free radical production and subsequent toxic insults are represented in a schematic depiction in Figure 2. Under physiological conditions, the efficiency of reducing oxygen during terminal oxidation is approximately 97–99%, while 1–3% undergo incomplete reduction to superoxide (O2•−), a highly reactive free radical. O2•− can be transformed into hydrogen peroxide (H2O2) both spontaneously and through a reaction catalyzed by mitochondrial manganese superoxide dismutase (Mn-SOD) in the matrix. H2O2 normally undergoes degradation by glutathione peroxidase (GPX) and catalase (CAT) enzymes, yielding water. In case of an impaired function of the mitochondrial ETC, leakage of excess electrons from complexes I and III leads to a higher amount of O2•− and subsequent H2O2 production, which when exceeding the degradative capacity of the mitochondria can be transformed into the extremely toxic hydroxyl radical (HO•), through reaction with transition metals (Fe2+ and Cu2+; Fenton reaction). HO• in turn can react with nucleic acids and phospholipids, yielding the formation of further toxic radicals and consequent severe functional impairments of the affected macromolecules. Furthermore, HO• can also react with thiol residues, yielding the formation of multiple reactive free radicals. In addition, O2•− can also react with nitric oxide (NO•) generated from L-arginine by mitochondrial nitric oxide synthase (mtNOS) enzyme [10]; however, other sources of mitochondrial NO• associated with nitrite reductase activity under hypoxic conditions have also been identified [11–13]. The reaction of NO• with O2•− yields the highly toxic peroxynitrite anion (ONOO−) in a reaction that is three times as fast as the dismutation of O2•− by Mn-SOD. ONOO− can evoke injury to proteins via nitration of tyrosine, tryptophan, and phenylalanine residues by nitronium ion (NO2+) generated through metal-peroxynitrite (ONOO−MenX) complexes. Nitration of tyrosine can also be achieved by serial reactions of further pathways involving ONOO− and NO• (see Figure 3 for detailed description). Nitrosylation of thiol, secondary amine, alcohol, and alkane residues are performed via their reaction with nitrosonium ion (NO+) or indirectly with dinitrogen trioxide (N2O3), highly reactive radicals also derived from NO•. Furthermore, NO• can directly impair the mitochondrial ETC and OXPHOS via competing with oxygen for the oxygen-binding site of complex IV [14], which leads to a further increase in free radical production.


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

Szalárdy L, Zádori D, Klivényi P, Toldi J, Vécsei L - Oxid Med Cell Longev (2015)

Schematic representation of the generation and the effects of free radicals within the mitochondria. The leakage of electrons from the mitochondrial ETC at complexes I and III results in the formation of superoxide anion. The high reactivity of this molecule evokes a harmful cascade mechanism including the formation of reactive oxygen and nitrogen species. The cascade mechanism deteriorates the functional groups of major components of all kinds of biomolecules (carbohydrates, lipids, proteins, and nucleic acids). In case of pronounced electron leakage or deficient antioxidant protection, a vicious circle of mitochondrial dysfunction develops.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537740&req=5

fig2: Schematic representation of the generation and the effects of free radicals within the mitochondria. The leakage of electrons from the mitochondrial ETC at complexes I and III results in the formation of superoxide anion. The high reactivity of this molecule evokes a harmful cascade mechanism including the formation of reactive oxygen and nitrogen species. The cascade mechanism deteriorates the functional groups of major components of all kinds of biomolecules (carbohydrates, lipids, proteins, and nucleic acids). In case of pronounced electron leakage or deficient antioxidant protection, a vicious circle of mitochondrial dysfunction develops.
Mentions: Free radicals are molecules possessing unpaired electrons in their outer orbit. This renders them highly reactive towards organic macromolecules such as carbohydrates, nucleic acids, proteins, and lipids, which suffer “injury” during such a reaction. The main routes of free radical production and subsequent toxic insults are represented in a schematic depiction in Figure 2. Under physiological conditions, the efficiency of reducing oxygen during terminal oxidation is approximately 97–99%, while 1–3% undergo incomplete reduction to superoxide (O2•−), a highly reactive free radical. O2•− can be transformed into hydrogen peroxide (H2O2) both spontaneously and through a reaction catalyzed by mitochondrial manganese superoxide dismutase (Mn-SOD) in the matrix. H2O2 normally undergoes degradation by glutathione peroxidase (GPX) and catalase (CAT) enzymes, yielding water. In case of an impaired function of the mitochondrial ETC, leakage of excess electrons from complexes I and III leads to a higher amount of O2•− and subsequent H2O2 production, which when exceeding the degradative capacity of the mitochondria can be transformed into the extremely toxic hydroxyl radical (HO•), through reaction with transition metals (Fe2+ and Cu2+; Fenton reaction). HO• in turn can react with nucleic acids and phospholipids, yielding the formation of further toxic radicals and consequent severe functional impairments of the affected macromolecules. Furthermore, HO• can also react with thiol residues, yielding the formation of multiple reactive free radicals. In addition, O2•− can also react with nitric oxide (NO•) generated from L-arginine by mitochondrial nitric oxide synthase (mtNOS) enzyme [10]; however, other sources of mitochondrial NO• associated with nitrite reductase activity under hypoxic conditions have also been identified [11–13]. The reaction of NO• with O2•− yields the highly toxic peroxynitrite anion (ONOO−) in a reaction that is three times as fast as the dismutation of O2•− by Mn-SOD. ONOO− can evoke injury to proteins via nitration of tyrosine, tryptophan, and phenylalanine residues by nitronium ion (NO2+) generated through metal-peroxynitrite (ONOO−MenX) complexes. Nitration of tyrosine can also be achieved by serial reactions of further pathways involving ONOO− and NO• (see Figure 3 for detailed description). Nitrosylation of thiol, secondary amine, alcohol, and alkane residues are performed via their reaction with nitrosonium ion (NO+) or indirectly with dinitrogen trioxide (N2O3), highly reactive radicals also derived from NO•. Furthermore, NO• can directly impair the mitochondrial ETC and OXPHOS via competing with oxygen for the oxygen-binding site of complex IV [14], which leads to a further increase in free radical production.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, Szeged 6725, Hungary.

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.

No MeSH data available.


Related in: MedlinePlus