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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

The involvement of mitochondrial dysfunction in Huntington's disease. Complex II deficiency, the predominant electron transport disorder in HD has long been linked to the deleterious effects of mutant huntingtin aggregation, a pathognomonic alteration in HD, and inhibitors of complex II (such as 3-nitropropionic acid (3-NP) and malonate) are used in experimental modeling of the disease. Disturbed OXPHOS in the affected cells can lead to the development of a vicious circle, eventually leading to cell death. Novel findings link PGC-1α dysfunction to the pathogenesis of HD at multiple levels, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)
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fig5: The involvement of mitochondrial dysfunction in Huntington's disease. Complex II deficiency, the predominant electron transport disorder in HD has long been linked to the deleterious effects of mutant huntingtin aggregation, a pathognomonic alteration in HD, and inhibitors of complex II (such as 3-nitropropionic acid (3-NP) and malonate) are used in experimental modeling of the disease. Disturbed OXPHOS in the affected cells can lead to the development of a vicious circle, eventually leading to cell death. Novel findings link PGC-1α dysfunction to the pathogenesis of HD at multiple levels, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)

Mentions: Huntington's disease (HD) is a monogenic, progressive neurodegenerative disease of autosomal dominant inheritance. The genetic alteration is the expansion of CAG trinucleotide repeat sequence on the interesting transcript 15 (IT15) gene on chromosome 4 encoding huntingtin, with increasing number of repeat associating with earlier onset and more rapid progression [133, 134]. The disease onset is usually between 40 and 50 years of age, presenting with behavioral alterations and hyperkinesia in the early stages, subsequently associating with pyramidal symptoms, dystonia, dementia, and psychosis. The pathognomonic alteration is the preferential loss of the striatal γ-aminobutyric acid (GABA)-ergic medium-sized spiny projection neurons (MSNs) and the presence of intracytoplasmic and intranuclear protein inclusions of mutant huntingtin widely distributed in neuronal as well as extraneuronal tissues. The characteristic decreased activity of respiratory complex II, especially in the striatum, has early linked HD to mitochondrial dysfunction [135] (Figure 5). Since then, deficiency in complex II is the most consistent and predominant alteration reported in HD; however, the involvement of other respiratory complexes has also been suggested [136, 137]. The concept of mitochondrial dysfunction mediating the pathological process induced by mutant huntingtin is consistent with an increased presence of oxidative stress [137–141], which is well-reflected by the increased amount of mtDNA mutations observed in HD patients [142]. Further alterations supporting the primary role of mitochondrial dysfunction in mediating the effects of mutant huntingtin include a transcriptional [143] and/or functional [144] repression of PGC-1α, disturbances in mitochondrial trafficking [145], a gradually decreasing mitochondrial number [146], and an impairment of mitochondrial calcium handling [147] with an enhanced sensitivity to calcium-induced opening of mPTP and cytochrome c-mediated cell death [148, 149].


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)

The involvement of mitochondrial dysfunction in Huntington's disease. Complex II deficiency, the predominant electron transport disorder in HD has long been linked to the deleterious effects of mutant huntingtin aggregation, a pathognomonic alteration in HD, and inhibitors of complex II (such as 3-nitropropionic acid (3-NP) and malonate) are used in experimental modeling of the disease. Disturbed OXPHOS in the affected cells can lead to the development of a vicious circle, eventually leading to cell death. Novel findings link PGC-1α dysfunction to the pathogenesis of HD at multiple levels, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: The involvement of mitochondrial dysfunction in Huntington's disease. Complex II deficiency, the predominant electron transport disorder in HD has long been linked to the deleterious effects of mutant huntingtin aggregation, a pathognomonic alteration in HD, and inhibitors of complex II (such as 3-nitropropionic acid (3-NP) and malonate) are used in experimental modeling of the disease. Disturbed OXPHOS in the affected cells can lead to the development of a vicious circle, eventually leading to cell death. Novel findings link PGC-1α dysfunction to the pathogenesis of HD at multiple levels, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)
Mentions: Huntington's disease (HD) is a monogenic, progressive neurodegenerative disease of autosomal dominant inheritance. The genetic alteration is the expansion of CAG trinucleotide repeat sequence on the interesting transcript 15 (IT15) gene on chromosome 4 encoding huntingtin, with increasing number of repeat associating with earlier onset and more rapid progression [133, 134]. The disease onset is usually between 40 and 50 years of age, presenting with behavioral alterations and hyperkinesia in the early stages, subsequently associating with pyramidal symptoms, dystonia, dementia, and psychosis. The pathognomonic alteration is the preferential loss of the striatal γ-aminobutyric acid (GABA)-ergic medium-sized spiny projection neurons (MSNs) and the presence of intracytoplasmic and intranuclear protein inclusions of mutant huntingtin widely distributed in neuronal as well as extraneuronal tissues. The characteristic decreased activity of respiratory complex II, especially in the striatum, has early linked HD to mitochondrial dysfunction [135] (Figure 5). Since then, deficiency in complex II is the most consistent and predominant alteration reported in HD; however, the involvement of other respiratory complexes has also been suggested [136, 137]. The concept of mitochondrial dysfunction mediating the pathological process induced by mutant huntingtin is consistent with an increased presence of oxidative stress [137–141], which is well-reflected by the increased amount of mtDNA mutations observed in HD patients [142]. Further alterations supporting the primary role of mitochondrial dysfunction in mediating the effects of mutant huntingtin include a transcriptional [143] and/or functional [144] repression of PGC-1α, disturbances in mitochondrial trafficking [145], a gradually decreasing mitochondrial number [146], and an impairment of mitochondrial calcium handling [147] with an enhanced sensitivity to calcium-induced opening of mPTP and cytochrome c-mediated cell death [148, 149].

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