NHE-1 inhibition improves cardiac mitochondrial function through regulation of mitochondrial biogenesis during postinfarction remodeling

2006 ◽  
Vol 291 (4) ◽  
pp. H1722-H1730 ◽  
Author(s):  
Sabzali Javadov ◽  
Daniel M. Purdham ◽  
Asad Zeidan ◽  
Morris Karmazyn
Keyword(s):  
Transcription Factors ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Marker Gene ◽  
Specific Inhibitor ◽  
Coronary Artery Ligation ◽  
Strong Positive Correlation ◽  
Mitochondrial Transcription ◽  
Postinfarction Remodeling ◽  
Mitochondrial Respiratory

We have recently demonstrated that mitochondrial respiratory dysfunction and mitochondrial permeability transition pore opening during postinfarction remodeling are prevented by the Na+/H+ exchange-1 (NHE-1)-specific inhibitor EMD-87580 (EMD). One of the mechanisms underlying the beneficial effect of NHE-1 inhibition on mitochondria could result from the drug's ability to regulate transcriptional factors responsible for mitochondrial function. In the present study, the effect of EMD on the expression of nuclear factors involved in mitochondrial biogenesis and expression of nuclear (COXNUCSUB IV) and mitochondrial (COXMITSUB I) encoded cytochrome c oxidase subunits has been studied in rat hearts subjected to either 12 or 18 wk of coronary artery ligation (CAL). Remodeling induced an increase in expression of the hypertrophic marker gene atrial natriuretic peptide, especially 12 wk after CAL. The mRNA level of the peroxisome proliferator-activated receptor-γ coactivator-1α and its downstream factors, including nuclear respiratory factor 1 and 2, mitochondrial transcription factor A, COXNUCSUB IV, and COXMITSUB I, were significantly reduced in hearts both 12 and 18 wk after ligation compared with sham-operated hearts. Dietary EMD provided immediately after ligation attenuated downregulation of mitochondrial transcription factors with a parallel decrease of hypertrophic marker gene expression. Regression analysis demonstrated a strong positive correlation between the transcription factors and mitochondrial respiratory function. Thus our study shows that the downregulation of mitochondrial transcription factors induced by postinfarction remodeling can be significantly attenuated by NHE-1 inhibition with a further improvement of mitochondrial function in these hearts.

scholarly journals Control of Mitochondrial Transcription Specificity Factors (TFB1M and TFB2M) by Nuclear Respiratory Factors (NRF-1 and NRF-2) and PGC-1 Family Coactivators

2005 ◽  
Vol 25 (4) ◽  
pp. 1354-1366 ◽  
Author(s):  
Natalie Gleyzer ◽  
Kristel Vercauteren ◽  
Richard C. Scarpulla
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase ◽  
Mitochondrial Biogenesis ◽  
Mammalian Cells ◽  
Cellular Systems ◽  
Mitochondrial Rna ◽  
Mitochondrial Transcription ◽  
Nuclear Respiratory Factors ◽  
Mitochondrial Rna Polymerase ◽  
Mtdna Transcription

ABSTRACT In vertebrates, mitochondrial DNA (mtDNA) transcription is initiated bidirectionally from closely spaced promoters, HSP and LSP, within the D-loop regulatory region. Early studies demonstrated that mtDNA transcription requires mitochondrial RNA polymerase and Tfam, a DNA binding stimulatory factor that is required for mtDNA maintenance. Recently, mitochondrial transcription specificity factors (TFB1M and TFB2M), which markedly enhance mtDNA transcription in the presence of Tfam and mitochondrial RNA polymerase, have been identified in mammalian cells. Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1α and PRC. The physiological induction of these coactivators has been associated with the integration of NRFs and other transcription factors in a program of mitochondrial biogenesis. Finally, we demonstrate that the TFB genes are up-regulated along with Tfam and either PGC-1α or PRC in cellular systems where mitochondrial biogenesis is induced. Moreover, ectopic expression of PGC-1α is sufficient to induce the coordinate expression of all three nucleus-encoded mitochondrial transcription factors along with nuclear and mitochondrial respiratory subunits. These results support the conclusion that the coordinate regulation of nucleus-encoded mitochondrial transcription factors by NRFs and PGC-1 family coactivators is essential to the control of mitochondrial biogenesis.

scholarly journals Hypoxia-mediated regulation of mitochondrial transcription factors: Implications for hypertensive renal physiology

2019 ◽  
Author(s):  
Bhargavi Natarajan ◽  
Vikas Arige ◽  
Abrar A. Khan ◽  
S. Santosh Reddy ◽  
Rashmi Santhoshkumar ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Mitochondrial Function ◽  
Energy Demand ◽  
Acute Hypoxia ◽  
Renal Physiology ◽  
Sodium Reabsorption ◽  
Tubular Damage ◽  
Hypertensive Rats ◽  
Mitochondrial Transcription ◽  
Renal Tubular

AbstractKidneys have a high resting metabolic rate and low tissue partial pressure of oxygen due to enhanced mitochondrial oxygen consumption and ATP production for active solute transport. Enhanced mitochondrial activity leads to progressive hypoxia from the renal cortex to renal medulla. Renal tubulointerstitial hypoxia (TiH) is severe in hypertensive rats due to increased sodium reabsorption within their nephrons. Additionally, these rats display increased energy demand and therefore, require healthy mitochondria for adequate salt reabsorption. Hence, we sought to study the regulation of mitochondrial biogenesis and expression of mitochondrial transcription factors (mtTFs, viz. Tfam, Tfb1m and Tfb2m) during hypoxic conditions and in rodent models of genetic hypertension. We report that the expressions of HIF-1α (hypoxia inducible factor-1α), PGC-1α (peroxisome proliferator activated receptor-γ co-activator-1α), mtTFs and OXPHOS proteins are elevated in hypertensive rats as compared to their normotensive counterparts. Additionally, studies in cultured kidney cells show that acute hypoxia augments the expression of these genes. We also observe a positive correlation between HIF-1α and mtTFs transcripts in human tissues. Furthermore, we report for the first time to our knowledge, that HIF-1α binds to promoters of Tfam, Tfb1m and Tfb2m genes and augments their promoter activities in NRK52e cells subjected to acute hypoxia. Taken together, this study suggests that acute hypoxia may enhance mitochondrial function to meet the energy demand in renal tubular epithelial cells and in young/pre-hypertensive SHR kidneys.Translational StatementOur results suggest that tubulointerstitial hypoxia (TiH) prevailing in prehypertensive rats augments the expression of mitochondrial transcription factors and proteins of electron transport chain. Moreover, previous reports indicate that ATP synthesis in these rats are elevated. Thus, our study provides insights into the molecular mechanism of such enhanced mitochondrial function. We propose that during early stages of kidney diseases (marked by mild TiH) an enhancement of mitochondrial function via stimulation of HIF-1α/PGC-1α production may delay renal tubular damage.

Impact of endurance training on murine spontaneous activity, muscle mitochondrial DNA abundance, gene transcripts, and function

2007 ◽  
Vol 102 (3) ◽  
pp. 1078-1089 ◽  
Author(s):  
Lisa S. Chow ◽  
Laura J. Greenlund ◽  
Yan W. Asmann ◽  
Kevin R. Short ◽  
Shelly K. McCrady ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Transcription Factors ◽  
Glucose Tolerance ◽  
Mitochondrial Function ◽  
Aerobic Exercise Training ◽  
Gene Transcript ◽  
Related Gene ◽  
Mitochondrial Transcription ◽  
Transcript Levels ◽  
Gene Transcripts

We hypothesized that enhanced skeletal muscle mitochondrial function following aerobic exercise training is related to an increase in mitochondrial transcription factors, DNA abundance [mitochondrial DNA (mtDNA)], and mitochondria-related gene transcript levels, as well as spontaneous physical activity (SPA) levels. We report the effects of daily treadmill training on 12-wk-old FVB mice for 5 days/wk over 8 wk at 80% peak O2 consumption and studied the training effect on changes in body composition, glucose tolerance, muscle mtDNA muscle, mitochondria-related gene transcripts, in vitro muscle mitochondrial ATP production capacity (MATPC), and SPA levels. Compared with the untrained mice, the trained mice had higher peak O2 consumption (+18%; P < 0.001), lower percentage of abdominal (−25.4%; P < 0.02) and body fat (−19.5%; P < 0.01), improved glucose tolerance ( P < 0.04), and higher muscle mitochondrial enzyme activity (+19.5–43.8%; P < 0.04) and MATPC (+28.9 to +32.4%; P < 0.01). Gene array analysis showed significant differences in mRNAs of mitochondria-related ontology groups between the trained and untrained mice. Training also increased muscle mtDNA (+88.4 to +110%; P < 0.05), peroxisome proliferative-activated receptor-γ coactivator-1α protein (+99.5%; P < 0.04), and mitochondrial transcription factor A mRNA levels (+21.7%; P < 0.004) levels. SPA levels were higher in trained mice ( P = 0.056, two-sided t-test) and significantly correlated with two separate substrate-based measurements of MATPC ( P < 0.02). In conclusion, aerobic exercise training enhances muscle mitochondrial transcription factors, mtDNA abundance, mitochondria-related gene transcript levels, and mitochondrial function, and this enhancement in mitochondrial function occurs in association with increased SPA.

scholarly journals Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle

2004 ◽  
Vol 63 (2) ◽  
pp. 275-278 ◽  
Author(s):  
Edward O. Ojuka
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Glucose Transport ◽  
Mitochondrial Biogenesis ◽  
High Energy ◽  
Amp Kinase ◽  
Mitochondrial Transcription ◽  
L6 Myotubes ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A

Contractile activity induces mitochondrial biogenesis and increases glucose transport capacity in muscle. There has been much research on the mechanisms responsible for these adaptations. The present paper reviews the evidence, which indicates that the decrease in the levels of high-energy phosphates, leading to activation of AMP kinase (AMPK), and the increase in cytosolic Ca2+, which activates Ca2+/calmodulin-dependent protein kinase (CAMK), are signals that initiate these adaptative responses. Although the events downstream of AMPK and CAMK have not been well characterized, these events lead to activation of various transcription factors, including: nuclear respiratory factors (NRF) 1 and 2, which cause increased expression of proteins of the respiratory chain; PPAR-α, which up regulates the levels of enzymes of β oxidation; mitochondrial transcription factor A, which activates expression of the mitochondrial genome; myocyte-enhancing factor 2A, the transcription factor that regulates GLUT4 expression. The well-orchestrated expression of the multitude of proteins involved in these adaptations is mediated by the rapid activation of PPARγ co-activator (PGC) 1, a protein that binds to various transcription factors to maximize transcriptional activity. Activating AMPK using 5-aminoimidizole-4-carboxamide-1-β-D-riboside (AICAR) and increasing cytoplasmic Ca2+using caffeine, W7 or ionomycin in L6 myotubes increases the concentration of mitochondrial enzymes and GLUT4 and enhances the binding of NRF-1 and NRF-2 to DNA. AICAR and Ca-releasing agents also increase the levels of PGC-1, mitochondrial transcription factor A and myocyte-enhancing factors 2A and 2D. These results are similar to the responses seen in muscle during the adaptation to endurance exercise and show that L6 myotubes are a suitable model for studying the mechanisms by which exercise causes the adaptive responses in muscle mitochondria and glucose transport.

Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons

Pharmacology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Zhongyuan Piao ◽  
Lin Song ◽  
Lifen Yao ◽  
Limei Zhang ◽  
Yichan Lu
Keyword(s):  
Energy Metabolism ◽  
Cytochrome C ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Citrate Synthase ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Mitochondrial Functions ◽  
Primary Hippocampal Neurons

Introduction: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer’s disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders. Objective: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons. Methods: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1–42 (Aβ1–42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1–42 oligomer-treated neurons. Results and Conclusions: Our findings indicated that schisandrin significantly alleviated the Aβ1–42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

scholarly journals Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liselotte Bruun Christiansen ◽  
Tine Lovsø Dohlmann ◽  
Trine Pagh Ludvigsen ◽  
Ewa Parfieniuk ◽  
Michal Ciborowski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Obese Group ◽  
Control Group ◽  
Dependent Manner ◽  
Respiratory Capacity ◽  
Protein Carbonyl Content ◽  
Functional Changes ◽  
Mitochondrial Respiratory

AbstractStatins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.

Selected Contribution: Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle

2001 ◽  
Vol 90 (1) ◽  
pp. 389-396 ◽  
Author(s):  
Joe W. Gordon ◽  
Arne A. Rungi ◽  
Hidetoshi Inagaki ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Regulatory Protein ◽  
Mrna Levels ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A ◽  
Mitochondrial Transcript

Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is imported into mitochondria and is required for the transcription of mitochondrial DNA (mtDNA). We hypothesized that conditions known to produce mitochondrial biogenesis in skeletal muscle would be preceded by an increase in Tfam expression. Therefore, rat muscle was stimulated (10 Hz, 3 h/day). Tfam mRNA levels were significantly elevated (by 55%) at 4 days and returned to control levels at 14 days. Tfam import into intermyofibrillar (IMF) mitochondria was increased by 52 and 61% ( P < 0.05) at 5 and 7 days, respectively. This corresponded to an increase in the level of import machinery components. Immunoblotting data indicated that IMF Tfam protein content was increased by 63% ( P < 0.05) at 7 days of stimulation. This was associated with a 49% ( P < 0.05) increase in complex formation at the mtDNA promoter and a 65% ( P< 0.05) increase in the levels of a mitochondrial transcript, cytochrome- c oxidase (COX) subunit III. Similarly, COX enzyme activity was elevated by 71% ( P < 0.05) after 7 days of contractile activity. These results indicate that early events in mitochondrial biogenesis include increases in Tfam mRNA, followed by accelerations in mitochondrial import and increased Tfam content, which correspond with increased binding to the mtDNA promoter region. This was accompanied by increased mitochondrial transcript levels and elevated COX activity. These data support the role of Tfam as a regulatory protein involved in contractile activity-induced mitochondrial biogenesis.

scholarly journals Estradiol treatment or modest exercise improves hepatic health and mitochondrial outcomes in female mice following ovariectomy

2021 ◽  
Author(s):  
Kelly N. Z. Fuller ◽  
Colin S. McCoin ◽  
Alex T. Von Schulze ◽  
Claire J. Houchen ◽  
Michael A. Choi ◽  
...  
Keyword(s):  
Bile Acid ◽  
Mitochondrial Function ◽  
High Fat Diet ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
High Fat ◽  
Estradiol Treatment ◽  
Respiratory Capacity ◽  
Female Mice ◽  
Mitochondrial Respiratory

We recently reported that compared to males, female mice have increased hepatic mitochondrial respiratory capacity and are protected against high-fat diet-induced steatosis. Here we sought to determine the role of estrogen in hepatic mitochondrial function, steatosis, and bile acid metabolism in female mice, as well as investigate potential benefits of exercise in the absence or presence of estrogen via ovariectomy (OVX). Female C57BL mice (n=6 per group) were randomly assigned to sham surgery (Sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy (OVX+Est). Half of the mice in each treatment group were sedentary (SED) or had access to voluntary wheel running (VWR). All mice were fed a high-fat diet (HFD) and were housed at thermoneutral temperatures. We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmitoylcarnitine as substrates. As expected, OVX mice presented with greater hepatic steatosis, weight gain, and fat mass gain compared to Sham and OVX+Est animals. Hepatic mitochondrial coupling (Basal/State 3 respiration) with pyruvate was impaired following OVX, but both VWR and estradiol treatment rescued coupling to levels greater than or equal to Sham animals. Estradiol and exercise also had different effects on liver electron transport chain protein expression depending on OVX status. Markers of bile acid metabolism and excretion were also impaired by ovariectomy but rescued with estradiol add-back. Together our data suggest that estrogen depletion impairs hepatic mitochondrial function and liver health, and that estradiol replacement and modest exercise can aid in rescuing this phenotype.

scholarly journals DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

2021 ◽  
Vol 9 ◽  
Author(s):  
Sophia Bam ◽  
Erin Buchanan ◽  
Caitlyn Mahony ◽  
Colleen O’Ryan
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Autism Spectrum ◽  
Differential Methylation ◽  
Mtdna Copy Number ◽  
Key Genes

Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p &lt; 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10–6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p &lt; 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

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