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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 PGC-1α cascade. Transcriptional upregulation or posttranslational activation of PGC-1α due to fasting, physical exercise, cold exposure, or pharmacological manipulations leads to the transcriptional activation of several nuclear-encoded proteins involved in mitochondrial functioning at multiple levels, including mitochondrial biogenesis, adaptive metabolism, antioxidant responses, and proper ETC assembly/import.
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Related In: Results  -  Collection


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fig1: The PGC-1α cascade. Transcriptional upregulation or posttranslational activation of PGC-1α due to fasting, physical exercise, cold exposure, or pharmacological manipulations leads to the transcriptional activation of several nuclear-encoded proteins involved in mitochondrial functioning at multiple levels, including mitochondrial biogenesis, adaptive metabolism, antioxidant responses, and proper ETC assembly/import.

Mentions: In multicellular organisms, the ability to adaptively regulate and activate mitochondrial biogenesis and functions in response to a variety of conditions is essential to maintain energetic homeostasis and cellular viability. Several lines of evidence obtained in the past decade suggest that peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator 1-alpha (PGC-1α), a nuclear-encoded coactivator of a wide range of transcriptional factors, plays a key role in the transcriptional cascade of such adaptive processes. PGC-1α-mediated coactivation of genes such as nuclear respiratory factor 1 and 2 (NRF-1, -2), PPARs, estrogen-related receptors (ERRs), and myocyte-specific enhancer factor 2C (MEF2C) leads to an increased expression of a wide range of proteins involved in mitochondrial transcription, replication, and the import and assembly of a number of nuclear-encoded respiratory complex subunits; furthermore, it boosts OXPHOS and thermoregulation in a tissue-dependent manner, enhances gluconeogenesis and fatty acid oxidation [5], and increase oxidative stress defense [6] (Figure 1). The inducing effect of physical exercise (mediated by calcineurin A-linked MEF2 activity, calcium/calmodulin-dependent protein kinase IV- (CaMKIV-) linked cyclic AMP (cAMP) response element-binding protein (CREB) activity, and a p38 mitogen-activated protein kinase- (MAPK-) linked activating transcription factor 2 (ATF-2) activity), cold exposure and starvation (mediated by catecholamine- and glucagon-induced cAMP elevation and a subsequent phosphorylation and activation of CREB by protein kinase A (PKA)) on PGC-1α expression is well documented [5]. Furthermore, energy deprivation through a high AMP/ATP ratio leads to an increased AMP-activated protein kinase (AMPK) activity and a subsequent phosphorylation of PGC-1α protein, priming PGC-1α for subsequent deacetylation and thereby activation by silent information regulator 2 homolog 1 (Sirt-1) [7, 8], the expression of which is also increased in conditions with energy shortage, such as, starvation or exercise, due to a high NAD+/NADH ratio [9]. These posttranslational modifications on PGC-1α play pivotal roles in adaptive mitochondrial biogenesis. The roles of impaired mitochondrial function and more recently a decreased function of the PGC-1α cascade in the pathogenesis of degenerative CNS disorders are of extensive research interest.


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 PGC-1α cascade. Transcriptional upregulation or posttranslational activation of PGC-1α due to fasting, physical exercise, cold exposure, or pharmacological manipulations leads to the transcriptional activation of several nuclear-encoded proteins involved in mitochondrial functioning at multiple levels, including mitochondrial biogenesis, adaptive metabolism, antioxidant responses, and proper ETC assembly/import.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: The PGC-1α cascade. Transcriptional upregulation or posttranslational activation of PGC-1α due to fasting, physical exercise, cold exposure, or pharmacological manipulations leads to the transcriptional activation of several nuclear-encoded proteins involved in mitochondrial functioning at multiple levels, including mitochondrial biogenesis, adaptive metabolism, antioxidant responses, and proper ETC assembly/import.
Mentions: In multicellular organisms, the ability to adaptively regulate and activate mitochondrial biogenesis and functions in response to a variety of conditions is essential to maintain energetic homeostasis and cellular viability. Several lines of evidence obtained in the past decade suggest that peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator 1-alpha (PGC-1α), a nuclear-encoded coactivator of a wide range of transcriptional factors, plays a key role in the transcriptional cascade of such adaptive processes. PGC-1α-mediated coactivation of genes such as nuclear respiratory factor 1 and 2 (NRF-1, -2), PPARs, estrogen-related receptors (ERRs), and myocyte-specific enhancer factor 2C (MEF2C) leads to an increased expression of a wide range of proteins involved in mitochondrial transcription, replication, and the import and assembly of a number of nuclear-encoded respiratory complex subunits; furthermore, it boosts OXPHOS and thermoregulation in a tissue-dependent manner, enhances gluconeogenesis and fatty acid oxidation [5], and increase oxidative stress defense [6] (Figure 1). The inducing effect of physical exercise (mediated by calcineurin A-linked MEF2 activity, calcium/calmodulin-dependent protein kinase IV- (CaMKIV-) linked cyclic AMP (cAMP) response element-binding protein (CREB) activity, and a p38 mitogen-activated protein kinase- (MAPK-) linked activating transcription factor 2 (ATF-2) activity), cold exposure and starvation (mediated by catecholamine- and glucagon-induced cAMP elevation and a subsequent phosphorylation and activation of CREB by protein kinase A (PKA)) on PGC-1α expression is well documented [5]. Furthermore, energy deprivation through a high AMP/ATP ratio leads to an increased AMP-activated protein kinase (AMPK) activity and a subsequent phosphorylation of PGC-1α protein, priming PGC-1α for subsequent deacetylation and thereby activation by silent information regulator 2 homolog 1 (Sirt-1) [7, 8], the expression of which is also increased in conditions with energy shortage, such as, starvation or exercise, due to a high NAD+/NADH ratio [9]. These posttranslational modifications on PGC-1α play pivotal roles in adaptive mitochondrial biogenesis. The roles of impaired mitochondrial function and more recently a decreased function of the PGC-1α cascade in the pathogenesis of degenerative CNS disorders are of extensive research interest.

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