scholarly journals Neuron-Specific Mechanisms Control the Mitochondrial Regulator PGC-1a

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 983-983
Author(s):  
Eric McGregor ◽  
Dylan Souder ◽  
Josef Clark ◽  
Timothy Rhoads ◽  
Kevin Elicieri ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Metabolic Regulation ◽  
Brain Aging ◽  
Brain Size ◽  
Lithium Treatment ◽  
Peroxisome Proliferator ◽  
Transcriptional Coactivator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Transcript Variants ◽  
Species Production

Abstract Mitochondrial dysfunction has been proposed as a hallmark of the aging process. Specifically, as a function of aging, mitochondria appear to have decreased enzyme activity and respiratory capacity and increase reactive oxygen species production. Brain aging is associated with morphological and homeostatic changes, including alterations in brain size, cognitive impairment, and white and grey matter integrity. However, the causes of these changes remain an open and actively pursued field of study. The ubiquitously expressed transcriptional coactivator peroxisome proliferator-activated receptor gamma-coactivator 1 (PGC-1a) has been described as the master regulator of mitochondrial function. Despite the emerging connections between PGC-1a and disease vulnerability, the regulation of PGC-1a outside of the skeletal muscle, liver, and adipose tissue is not well defined. This is particularly true in the brain, where PGC-1a is enriched in neurons, and alterations in expression levels have been linked to neurodegenerative disorders. Here we report that astrocytes and neurons differ substantially in mitochondrial status and the transcript variants of PGC-1a expressed, including using a neuron-specific promoter. Taking advantage of the ability of the tau-kinase GSK-3b to influence PGC-1a expression, we investigate how transcript variants are differentially regulated in primary neurons and astrocytes. Neuronal PGC-1a responds robustly to GSK3b inhibition by lithium, switching the dominant promoter, leading to changes in isoform distribution and abundance, while astrocytes are refractory to lithium treatment. The data presented here highlight key mechanisms for neuron-specific metabolic regulation that are likely to be relevant to neurodegenerative diseases that have a link to mitochondrial dysfunction.

scholarly journals The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 934
Author(s):  
Woon-Man Kung ◽  
Muh-Shi Lin
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Management Strategies ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Proinflammatory Response ◽  
Pharmacological Management ◽  
Peroxisome Proliferator Activated Receptor ◽  
Iron Sulfur ◽  
Promising Target

Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.

scholarly journals BST204 Protects Dexamethasone-Induced Myotube Atrophy through the Upregulation of Myotube Formation and Mitochondrial Function

2021 ◽  
Vol 18 (5) ◽  
pp. 2367
Author(s):  
Ryuni Kim ◽  
Hyebeen Kim ◽  
Minju Im ◽  
Sun Kyu Park ◽  
Hae Jung Han ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Inflammatory Responses ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dry Extract ◽  
Myotube Formation ◽  
Species Production

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.

scholarly journals PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.

2021 ◽  
Author(s):  
Connie Anne Mackenzie-Gray Scott ◽  
Robert Ryley Parrish ◽  
Darren A Walsh ◽  
Claudia Racca ◽  
Rita M Cowell ◽  
...  
Keyword(s):  
Cortical Excitability ◽  
Energy Requirement ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Epileptic Activity ◽  
Synaptic Proteins ◽  
Peroxisome Proliferator ◽  
Transcriptional Coactivator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out

The transcriptional coactivator, PGC-1α (peroxisome proliferator activated receptor gamma coactivator 1α), plays a key role coordinating energy requirement within cells. Its importance is reflected in the growing number of psychiatric and neurological conditions that have been associated with reduced PGC-1α levels. In cortical networks, PGC-1α is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1a deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1α specifically in the PV-expressing cells (PGC-1αPV-/-) blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell-class specific knock-out of PGC-1α appears to have a novel anti-epileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of occurrence of pre-ictal discharges developed approximately equivalently in wild-type and PGC-1αPV-/- brain slices, but the intensity of these discharges was lower in PGC-1αPV-/- slices, as evident from the reduced power in the gamma range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the pre-ictal discharges, the PGC-1αPV-/- brain slices experienced many more discharges before transitioning into a seizure-like event. Consequently, there was a large increase in the latency to the first seizure-like event in brain slices lacking PGC-1α in PV interneurons. We conclude that knocking down PGC-1α limits the range of PV interneuron firing, and this slows the pathophysiological escalation during ictogenesis.

scholarly journals Metabolic regulation of exercise-induced angiogenesis

2019 ◽  
Vol 1 (1) ◽  
pp. H1-H8 ◽  
Author(s):  
Tatiane Gorski ◽  
Katrien De Bock
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Metabolic Reprogramming ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Valuable Insight ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced

Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. In skeletal muscle, angiogenesis can occur via sprouting and splitting angiogenesis and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation of Vegf expression and increased muscle capillary density. While ECs are highly glycolytic and change their metabolism during sprouting angiogenesis in development and disease, a similar role for EC metabolism in exercise-induced angiogenesis in skeletal muscle remains to be elucidated. Nonetheless, recent studies have illustrated the importance of endothelial hydrogen sulfide and sirtuin 1 (SIRT1) activity for exercise-induced angiogenesis, suggesting that EC metabolic reprogramming may be fundamental in this process. We hypothesize that the exercise-induced angiogenic response can also be modulated by metabolic crosstalk between muscle and the endothelium. Defining the underlying molecular mechanisms responsible for skeletal muscle angiogenesis in response to exercise will yield valuable insight into metabolic regulation as well as the determinants of exercise performance.

scholarly journals PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.

2021 ◽  
Author(s):  
R Ryley Parrish ◽  
Connie Mackenzie-Gray-Scott ◽  
Darren Walsh ◽  
Claudia Racca ◽  
Rita M Cowell ◽  
...  
Keyword(s):  
Cortical Excitability ◽  
Energy Requirement ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Epileptic Activity ◽  
Synaptic Proteins ◽  
Peroxisome Proliferator ◽  
Transcriptional Coactivator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out

The transcriptional coactivator, PGC-1α (peroxisome proliferator activated receptor gamma coactivator 1α), plays a key role coordinating energy requirement within cells. Its importance is reflected in the growing number of psychiatric and neurological conditions that have been associated with reduced PGC-1α levels. In cortical networks, PGC-1α is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1α deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1α specifically in the PV-expressing cells (PGC-1αPV-/-), blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell-class specific knock-out of PGC-1α appears to have a novel anti-epileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of pre-ictal discharges developed approximately equivalently in wild-type and PGC-1αPV-/- brain slices, but the intensity of these discharges was lower in PGC-1αPV-/- slices, as evident from the reduced power in the gamma range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the pre-ictal discharges, the PGC-1αPV-/- brain slices experienced many more discharges before transitioning into a seizure-like event. Consequently, there was a large increase in the latency to the first seizure-like event in brain slices lacking PGC-1α in PV interneurons. We conclude that knocking down PGC-1α limits the range of PV interneuron firing, and this slows the pathophysiological escalation during ictogenesis.

Activation of SIRT1 Alleviates Mitochondrial Dysfunction in The Trigeminal Nucleus Caudalis in a Rat Model of Chronic Migraine

2020 ◽  
Author(s):  
jie liang ◽  
xue zhou ◽  
jiang wang ◽  
zhaoyang fei ◽  
guangcheng qin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Chronic Migraine ◽  
Rat Model ◽  
Vital Role ◽  
Peroxisome Proliferator ◽  
Trigeminal Nucleus ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Respiratory Factor ◽  
Trigeminal Nucleus Caudalis ◽  
Nuclear Respiratory Factor 1

Abstract Background: The mechanism of chronic migraine (CM) is still unclear and mitochondrial dysfunction plays a possible role in migraine pathophysiology. Silent information regulator 1 (SIRT1) plays a vital role in mitochondrial dysfunction in many diseases, but there is no information about SIRT1 in CM.The aim of this study was to explore the role of SIRT1 in mitochondrial dysfunction in CM. Methods： A rat model was established through repeated dural infusions of inflammatory soup (IS) for seven days to simulate CM attacks. Cutaneous hyperalgesia caused by the repeated infusions of IS was detected using the von Frey test. Then, we detected SIRT1 expression in the trigeminal nucleus caudalis (TNC). To explore the effect of SIRT1 on mitochondrial dysfunction in CM rats, we examined whether SRT1720, an activator of SIRT1, altered mitochondrial dysfunction in CM rats. Results： Repeated infusions of IS resulted in cutaneous hyperalgesia accompanied bydownregulation of SIRT1.SRT1720 significantly alleviated the cutaneous hyperalgesia induced by repeated infusions of IS. Furthermore, activation of SIRT1 markedly increased the expression of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha(PGC-1α), transcription factor A (TFAM), nuclear respiratory factor 1 (NRF-1), and nuclear respiratory factor 2(NRF-2) mitochondrial DNA (mtDNA) and increased the ATP content and mitochondrial membrane potential. Conclusions ：Our results indicate that SIRT1 may have an effect on mitochondrial dysfunction in CM rats. Activation of SIRT1 has a protective effect on mitochondrial function in CM rats.

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