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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 Parkinson's disease. Complex I deficiency, the predominant electron transport disorder in sporadic PD has long been linked to the deleterious effects of α-synuclein aggregation, a pathognomonic alteration in PD, and inhibitors of complex I (such as MPTP, rotenone, and paraquat) are used in experimental modeling of the disease. Since then a number of genes have been associated with familial forms of the disease, many of them having direct implications in mitochondrial dysfunction. 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 sporadic PD, 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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fig4: The involvement of mitochondrial dysfunction in Parkinson's disease. Complex I deficiency, the predominant electron transport disorder in sporadic PD has long been linked to the deleterious effects of α-synuclein aggregation, a pathognomonic alteration in PD, and inhibitors of complex I (such as MPTP, rotenone, and paraquat) are used in experimental modeling of the disease. Since then a number of genes have been associated with familial forms of the disease, many of them having direct implications in mitochondrial dysfunction. 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 sporadic PD, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)

Mentions: Parkinson's disease (PD) is a progressive, chronic neurodegenerative disorder, the pathognomonic alterations of which include loss of dopaminergic neurons, and the presence of Lewy bodies in the substantia nigra pars compacta (SNpc), with a subsequent decrease in striatal dopamine levels [51]. Leading clinical symptoms include bradykinesia, rigidity, resting tremor, and postural instability [52, 53], eventually evolving into severe akinesia, dementia, and eventually death. The development of sporadic PD is linked to a complex interplay of genetic and environmental factors, which have multiple implications for mitochondrial involvement (Figure 4). The first implication for the role of mitochondrial dysfunction in PD came from serial cases of intoxication by the side-product of a synthetic illicit drug, MPTP, which evokes parkinsonian symptoms and recapitulates the majority of PD-related pathologies [54]. Its active metabolite 1-methyl-4-phenylpyridinium (MPP+) selectively and irreversibly impairs the function of mitochondrial complex I in dopaminergic neurons [55, 56], and since its discovery, systemic MPTP or intraventricular MPP+ intoxication became the most widely applied in vivo toxin models of PD. Similar effects can be achieved by known environmental chemicals including the herbicide paraquat and the insecticide rotenone [57]. Corresponding with the ability of complex I inhibitors to evoke parkinsonism, a decreased activity and/or expression of respiratory complex I has been detected in the SNpc [58, 59], striatum [60] frontal cortex [61], platelets [62, 63], and skeletal muscle [64, 65] of sporadic PD patients, suggesting a systemic impairment of mitochondrial functions in this disease. Less consistent reports have been published regarding the involvement of other respiratory complexes, which indicates a predominant involvement of complex I in sporadic PD. In line with these, a decreased activity of complex I, an elevated production of ROS, an energy impairment, and an increased sensitivity to MPP+ intoxication can be detected in PD cybrids [66, 67]. The increased presence of oxidative damage has also been reported in post mortem SN of PD patients [68, 69].


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 Parkinson's disease. Complex I deficiency, the predominant electron transport disorder in sporadic PD has long been linked to the deleterious effects of α-synuclein aggregation, a pathognomonic alteration in PD, and inhibitors of complex I (such as MPTP, rotenone, and paraquat) are used in experimental modeling of the disease. Since then a number of genes have been associated with familial forms of the disease, many of them having direct implications in mitochondrial dysfunction. 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 sporadic PD, 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

fig4: The involvement of mitochondrial dysfunction in Parkinson's disease. Complex I deficiency, the predominant electron transport disorder in sporadic PD has long been linked to the deleterious effects of α-synuclein aggregation, a pathognomonic alteration in PD, and inhibitors of complex I (such as MPTP, rotenone, and paraquat) are used in experimental modeling of the disease. Since then a number of genes have been associated with familial forms of the disease, many of them having direct implications in mitochondrial dysfunction. 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 sporadic PD, the restoration of which may hold therapeutic value. (↑ = increased presence/expression/activity; ↓ = decreased presence/expression/activity; arrow = promotion; bulb-headed arrow = inhibition/deterioration.)
Mentions: Parkinson's disease (PD) is a progressive, chronic neurodegenerative disorder, the pathognomonic alterations of which include loss of dopaminergic neurons, and the presence of Lewy bodies in the substantia nigra pars compacta (SNpc), with a subsequent decrease in striatal dopamine levels [51]. Leading clinical symptoms include bradykinesia, rigidity, resting tremor, and postural instability [52, 53], eventually evolving into severe akinesia, dementia, and eventually death. The development of sporadic PD is linked to a complex interplay of genetic and environmental factors, which have multiple implications for mitochondrial involvement (Figure 4). The first implication for the role of mitochondrial dysfunction in PD came from serial cases of intoxication by the side-product of a synthetic illicit drug, MPTP, which evokes parkinsonian symptoms and recapitulates the majority of PD-related pathologies [54]. Its active metabolite 1-methyl-4-phenylpyridinium (MPP+) selectively and irreversibly impairs the function of mitochondrial complex I in dopaminergic neurons [55, 56], and since its discovery, systemic MPTP or intraventricular MPP+ intoxication became the most widely applied in vivo toxin models of PD. Similar effects can be achieved by known environmental chemicals including the herbicide paraquat and the insecticide rotenone [57]. Corresponding with the ability of complex I inhibitors to evoke parkinsonism, a decreased activity and/or expression of respiratory complex I has been detected in the SNpc [58, 59], striatum [60] frontal cortex [61], platelets [62, 63], and skeletal muscle [64, 65] of sporadic PD patients, suggesting a systemic impairment of mitochondrial functions in this disease. Less consistent reports have been published regarding the involvement of other respiratory complexes, which indicates a predominant involvement of complex I in sporadic PD. In line with these, a decreased activity of complex I, an elevated production of ROS, an energy impairment, and an increased sensitivity to MPP+ intoxication can be detected in PD cybrids [66, 67]. The increased presence of oxidative damage has also been reported in post mortem SN of PD patients [68, 69].

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