Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

AbstractMitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrated that cocaine affects mitochondrial dynamics within the nucleus accumbens (NAc) and mitochondria are differentially regulated by cocaine in dopamine receptor-1 (D1) containing medium spiny neurons (MSNs) vs dopamine receptor-2 (D2)-MSNs. Here, it is demonstrated that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Further, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Subsequent experiments demonstrated that Egr3 overexpression in D1-MSNs enhances the expression of several mitochondrial-associated nuclear genes. By contrast, blunting Egr3 expression blocks cocaine enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reducing Egr3 expression attenuates the cocaine-induced enhancement of small-sized mitochondria, demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts and mitochondrial dynamics, with implications for mechanisms underlying neuronal function and plasticity occurring with cocaine exposure.

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Cocaine-induced neuron subtype mitochondrial dynamics through Egr3 transcriptional regulation

Molecular Brain ◽

10.1186/s13041-021-00800-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Shannon L. Cole ◽

Ramesh Chandra ◽

Maya Harris ◽

Ishan Patel ◽

Torrance Wang ◽

...

Keyword(s):

Transcriptional Regulation ◽

Dopamine Receptor ◽

Mitochondrial Function ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Morphological Characteristics ◽

Nuclear Gene ◽

Nuclear Genes ◽

Peroxisome Proliferator ◽

Cocaine Exposure

AbstractMitochondrial function is required for brain energy homeostasis and neuroadaptation. Recent studies demonstrate that cocaine affects mitochondrial dynamics and morphological characteristics within the nucleus accumbens (NAc). Further, mitochondria are differentially regulated by cocaine in dopamine receptor-1 containing medium spiny neurons (D1-MSNs) vs dopamine receptor-2 (D2)-MSNs. However, there is little understanding into cocaine-induced transcriptional mechanisms and their role in regulating mitochondrial processes. Here, we demonstrate that cocaine enhances binding of the transcription factor, early growth response factor 3 (Egr3), to nuclear genes involved in mitochondrial function and dynamics. Moreover, cocaine exposure regulates mRNA of these mitochondria-associated nuclear genes in both contingent or noncontingent cocaine administration and in both rodent models and human postmortem tissue. Interestingly, several mitochondrial nuclear genes showed distinct profiles of expression in D1-MSNs vs D2-MSNs, with cocaine exposure generally increasing mitochondrial-associated nuclear gene expression in D1-MSNs vs suppression in D2-MSNs. Further, blunting Egr3 expression in D1-MSNs blocks cocaine-enhancement of the mitochondrial-associated transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and the mitochondrial fission molecule, dynamin related protein 1 (Drp1). Finally, reduction of D1-MSN Egr3 expression attenuates cocaine-induced enhancement of small-sized mitochondria, causally demonstrating that Egr3 regulates mitochondrial morphological adaptations. Collectively, these studies demonstrate cocaine exposure impacts mitochondrial dynamics and morphology by Egr3 transcriptional regulation of mitochondria-related nuclear gene transcripts; indicating roles for these molecular mechanisms in neuronal function and plasticity occurring with cocaine exposure.

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The E3 ligase MARCH5 is a PPARγ target gene that regulates mitochondria and metabolism in adipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00394.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. E293-E304 ◽

Cited By ~ 1

Author(s):

Simon T. Bond ◽

Sarah C. Moody ◽

Yingying Liu ◽

Mete Civelek ◽

Claudio J. Villanueva ◽

...

Keyword(s):

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Mouse Strains ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Metabolic Genes ◽

And Function

Mitochondrial dynamics refers to the constant remodeling of mitochondrial populations by multiple cellular pathways that help maintain mitochondrial health and function. Disruptions in mitochondrial dynamics often lead to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins, including the E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5), are known to regulate mitochondrial dynamics; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ) during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression in vitro and in vivo alters mitochondrial function, affects cellular metabolism, and leads to differential regulation of several metabolic genes. Thus our data demonstrate an association between mitochondrial dynamics and metabolism that defines MARCH5 as a critical link between these interconnected pathways.

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Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

Cells ◽

10.3390/cells10020352 ◽

2021 ◽

Vol 10 (2) ◽

pp. 352

Author(s):

Laura J. McMeekin ◽

Stephanie N. Fox ◽

Stephanie M. Boas ◽

Rita M. Cowell

Keyword(s):

Transcriptional Regulation ◽

Mitochondrial Function ◽

Developmental Disorders ◽

Neuronal Cell ◽

Cell Types ◽

Peroxisome Proliferator ◽

Therapeutic Targeting ◽

Peroxisome Proliferator Activated Receptor ◽

Disease States ◽

Challenges And Opportunities

Substantial evidence indicates that mitochondrial impairment contributes to neuronal dysfunction and vulnerability in disease states, leading investigators to propose that the enhancement of mitochondrial function should be considered a strategy for neuroprotection. However, multiple attempts to improve mitochondrial function have failed to impact disease progression, suggesting that the biology underlying the normal regulation of mitochondrial pathways in neurons, and its dysfunction in disease, is more complex than initially thought. Here, we present the proteins and associated pathways involved in the transcriptional regulation of nuclear-encoded genes for mitochondrial function, with a focus on the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). We highlight PGC-1α’s roles in neuronal and non-neuronal cell types and discuss evidence for the dysregulation of PGC-1α-dependent pathways in Huntington’s Disease, Parkinson’s Disease, and developmental disorders, emphasizing the relationship between disease-specific cellular vulnerability and cell-type-specific patterns of PGC-1α expression. Finally, we discuss the challenges inherent to therapeutic targeting of PGC-1α-related transcriptional programs, considering the roles for neuron-enriched transcriptional coactivators in co-regulating mitochondrial and synaptic genes. This information will provide novel insights into the unique aspects of transcriptional regulation of mitochondrial function in neurons and the opportunities for therapeutic targeting of transcriptional pathways for neuroprotection.

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

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18052367 ◽

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.

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Abstract P172: Activation of Pgc1α by EET Stimulates Insulin Sensitivity, Normalizes Blood Pressure and Increases Mitochondrial Oxphos in Obese Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.p172 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Shailendra P Singh ◽

Maayan Waldman ◽

Joseph Schragenheim ◽

Lars Bellner ◽

Jian Cao ◽

...

Keyword(s):

Blood Pressure ◽

Insulin Sensitivity ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Fasting Blood Glucose ◽

Cardiovascular Complications ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose Levels ◽

Obesity In Mice

Background/Objectives: Obesity is a risk factor in the development of type 2 diabetes mellitus (DM2), which is associated with increased morbidity and mortality, predominantly as a result of cardiovascular complications. Increased adiposity is a systemic condition characterized by increased oxidative stress (ROS), inflammation, inhibition of anti-oxidant genes such as HO-1 and increased degradation of epoxyeicosatrienoic acids (EETs). Hypothesis: We postulate that EETs increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) activity, which controls mitochondrial function, oxidative metabolism and may also increase antioxidants and HO-1 gene expression. Methods: C57/B16 mice were fed a high fat (HF) diet for 26 wks. The protocol comprised three groups: A) WT, B) HF control and C) HF-treated with EET agonist (EET-A). Renal and visceral fat tissues were harvested to measure signaling protein. Consumption was measured at 6 and 24 wks. Mice were used to assess insulin levels, insulin sensitivity, blood pressure and mitochondrial OXPHOS and mitochondrial biogenesis (Mfn1, 2 and Opa1), and oxygen consumption (VO 2 ). Results: Animals on a HF diet exhibited increased body weight, fat content, fasting blood glucose levels, systolic blood pressure (BP) and a significant reduction in VO 2 . Administration of EET-A to HF-fed mice decreased the RQ (VCO 2 /VO 2 ) ratio and normalized BP. The HF diet produced increased levels of the adipogenic markers MEST, aP2, C/EBPα and FAS. EET-A attenuated these perturbations through an increase in renal and adipose tissue PGC1α levels. The EET-mediated HO-1 induction increased mitochondrial function as measured by OXPHOS, MnSOD and thermogenic genes, TFAM, UCP1 and SIRT 1. EET-A also increased adiponectin levels, and insulin receptor phosphorylation IRP Tyr 972 and 1146 and normalized glucose levels. Conclusion: These data show that an EET agonist increased PGC-1α-HO-1 levels thereby providing metabolic protection and increased VO 2 consumption in HF-induced obesity in mice. This novel finding suggests that the EET-mediated PGC-1α activation is essential to increase HO-1 levels, mitochondrial biogenesis, and to decrease mitochondrial ROS and adiposity.

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Diet Modifies Pioglitazone’s Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression

PPAR Research ◽

10.1155/2020/3817573 ◽

2020 ◽

Vol 2020 ◽

pp. 1-20

Author(s):

Sakil Kulkarni ◽

Jiansheng Huang ◽

Eric Tycksen ◽

Paul F. Cliften ◽

David A. Rudnick

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Transcriptional Regulation ◽

Mitochondrial Gene ◽

Peroxisome Proliferator ◽

Large Set ◽

Peroxisome Proliferator Activated Receptor ◽

Nonalcoholic Fatty Liver ◽

Hepatic Expression ◽

Insulin Resistant

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation.

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Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis

Clinical Science ◽

10.1042/cs20180873 ◽

2019 ◽

Vol 133 (3) ◽

pp. 531-544 ◽

Cited By ~ 9

Author(s):

Tzu-Hao Li ◽

Ying-Ying Yang ◽

Chia-Chang Huang ◽

Chih-Wei Liu ◽

Hung-Cheng Tsai ◽

...

Keyword(s):

Liver Injury ◽

Energy Homeostasis ◽

Intestinal Barrier ◽

Peroxisome Proliferator ◽

Intestinal Epithelial ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Steatohepatitis ◽

Ppar Agonists ◽

Apoptosis And Inflammation ◽

Adipose Dysfunction

Abstract Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.

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Peroxisome Proliferator-Activated Receptor γ and PGC-1α in Cancer: Dual Actions as Tumor Promoter and Suppressor

PPAR Research ◽

10.1155/2018/6727421 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 19

Author(s):

Seong-Hoon Yun ◽

Sang-Heum Han ◽

Joo-In Park

Keyword(s):

Metabolic Pathways ◽

Energy Homeostasis ◽

Tumor Promoter ◽

Clinical Implications ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Interacting Protein ◽

Action Mechanisms ◽

Important Regulator

Peroxisome proliferator-activated receptor γ (PPARγ) is part of a nuclear receptor superfamily that regulates gene expression involved in cell differentiation, proliferation, immune/inflammation response, and lipid metabolism. PPARγ coactivator-1α (PGC-1α), initially identified as a PPARγ-interacting protein, is an important regulator of diverse metabolic pathways, such as oxidative metabolism and energy homeostasis. The role of PGC-1α in diabetes, neurodegeneration, and cardiovascular disease is particularly well known. PGC-1α is also now known to play important roles in cancer, independent of the role of PPARγ in cancer. Though many researchers have studied the expression and clinical implications of PPARγ and PGC-1α in cancer, there are still many controversies about the role of PPARγ and PGC-1α in cancer. This review examines and summarizes some recent data on the role and action mechanisms of PPARγ and PGC-1α in cancer, respectively, particularly the recent progress in understanding the role of PPARγ in several cancers since our review was published in 2012.

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Dopamine directly increases mitochondrial mass and thermogenesis in brown adipocytes

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0159 ◽

2017 ◽

Vol 58 (2) ◽

pp. 57-66 ◽

Cited By ~ 11

Author(s):

Rose Kohlie ◽

Nina Perwitz ◽

Julia Resch ◽

Sebastian M Schmid ◽

Hendrik Lehnert ◽

...

Keyword(s):

P38 Mapk ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Peroxisome Proliferator ◽

Cellular Mechanisms ◽

Brown Adipocytes ◽

Peroxisome Proliferator Activated Receptor ◽

Mitochondrial Mass ◽

Brown Adipose

Brown adipose tissue (BAT) is key to energy homeostasis. By virtue of its thermogenic potential, it may dissipate excessive energy, regulate body weight and increase insulin sensitivity. Catecholamines are critically involved in the regulation of BAT thermogenesis, yet research has focussed on the effects of noradrenaline and adrenaline. Some evidence suggests a role of dopamine (DA) in BAT thermogenesis, but the cellular mechanisms involved have not been addressed. We employed our extensively characterised murine brown adipocyte cells. D1-like and D2-like receptors were detectable at the protein level. Stimulation with DA caused an increase in cAMP concentrations. Oxygen consumption rates (OCR), mitochondrial membrane potential (Δψm) and uncoupling protein 1 (UCP1) levels increased after 24 h of treatment with either DA or a D1-like specific receptor agonist. A D1-like receptor antagonist abolished the DA-mediated effect on OCR, Δψm and UCP1. DA induced the release of fatty acids, which did not additionally alter DA-mediated increases of OCR. Mitochondrial mass (as determined by (i) CCCP- and oligomycin-mediated effects on OCR and (ii) immunoblot analysis of mitochondrial proteins) also increased within 24 h. This was accompanied by an increase in peroxisome proliferator-activated receptor gamma co-activator 1 alpha protein levels. Also, DA caused an increase in p38 MAPK phosphorylation and pharmacological inhibition of p38 MAPK abolished the DA-mediated effect on Δψm. In summary, our study is the first to reveal direct D1-like receptor and p38 MAPK-mediated increases of thermogenesis and mitochondrial mass in brown adipocytes. These results expand our understanding of catecholaminergic effects on BAT thermogenesis.

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