scholarly journals Changes in PGC-1α-Dependent Mitochondrial Biogenesis Are Associated with Inflexible Hepatic Energy Metabolism in the Offspring Born to Dexamethasone-Treated Mothers

Livers ◽  
2021 ◽  
Vol 1 (4) ◽  
pp. 201-220
Author(s):  
Carolina Vieira Campos ◽  
Caio Jordão Teixeira ◽  
Tanyara Baliani Payolla ◽  
Amanda Rabello Crisma ◽  
Gilson Masahiro Murata ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Biogenesis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Metabolic Response ◽  
In Utero ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hepatic Energy Metabolism ◽  
Neonatal Liver ◽  
Tag Accumulation

In the present study we investigated the participation of hepatic peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) in the metabolic programming of newborn rats exposed in utero to dexamethasone (DEX). On the 21st day of life, fasted offspring born to DEX-treated mothers displayed increased conversion of pyruvate into glucose with simultaneous upregulation of PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). Increased oxidative phosphorylation, higher ATP/ADP ratio and mitochondrial biogenesis and lower pyruvate levels were also found in the progeny of DEX-treated mothers. On the other hand, the 21-day-old progeny of DEX-treated mothers had increased hepatic triglycerides (TAG) and lower CPT-1 activity when subjected to short-term fasting. At the mechanistic level, rats exposed in utero to DEX exhibited increased hepatic PGC-1α protein content with lower miR-29a-c expression. Increased PGC-1α content was concurrent with increased association to HNF-4α and NRF1 and reduced PPARα expression. The data presented herein reveal that changes in the transcription machinery in neonatal liver of rats born to DEX-treated mothers leads to an inflexible metabolic response to fasting. Such programming is hallmarked by increased oxidative phosphorylation of pyruvate with impaired FFA oxidation and hepatic TAG accumulation.

scholarly journals Mitochondrial differentiation and oxidative phosphorylation system capacity in rat embryo during placentation period

Reproduction ◽  
2007 ◽  
Vol 134 (1) ◽  
pp. 147-154 ◽  
Author(s):  
M P Alcolea ◽  
B Colom ◽  
I Lladó ◽  
F J García-Palmer ◽  
M Gianotti
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Biogenesis ◽  
Transcriptional Activation ◽  
Oxidative Metabolism ◽  
System Capacity ◽  
Peroxisome Proliferator ◽  
Rat Embryo ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidative Phosphorylation System ◽  
Oxidase Subunit

Mitochondrial biogenesis and function are essential for proper embryo development; however, these processes have not been further studied during the placentation period, when important oxidative metabolism activation is taking place. Thus, the aim of the present study was to investigate the oxidative phosphorylation system (OXPHOS) enzymatic activities as well as the expression of genes involved in the coordinated regulation of both mitochondrial and nuclear genomes (peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factors 1 and 2, mitochondrial single-strand DNA-binding protein, mitochondrial transcription factor A), and mitochondrial function (cytochrome c oxidase subunit IV, cytochrome c oxidase subunit I and β-ATP phosphohydrolase) in rat embryo throughout the placentation period (gestational days 11, 12 and 13). Our results reflect that embryo mitochondria were enhancing their OXPHOS potential capacities, pointing out that embryo mitochondria become more differentiated during the placentation period. Besides, the current findings show that the mRNAs of the nuclear genes involved in mitochondrial biogenesis were downregulated, whereas their protein content together with the mitochondrial DNA expression were upregulated throughout the period studied. These data indicate that the molecular regulation of the mitochondrial differentiation process during placentation involves a post-transcriptional activation of the nuclear-encoded genes that would lead to an increase in both the nuclear- and mitochondrial-encoded proteins responsible for the mitochondrial biogenic process. As a result, embryo mitochondria would reach a more differentiated stage with a more efficient oxidative metabolism that would facilitate the important embryo growth during the second half of the pregnancy.

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer’s Disease

2021 ◽  
pp. 1-9
Author(s):  
Fan Ye ◽  
Anshi Wu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Biogenesis ◽  
Stress Responses ◽  
Histone Deacetylases ◽  
Neuronal Morphology ◽  
Protective Mechanism ◽  
Peroxisome Proliferator ◽  
Class Iii ◽  
Peroxisome Proliferator Activated Receptor

Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease

scholarly journals Progressive Reduction in Mitochondrial Mass Is Triggered by Alterations in Mitochondrial Biogenesis and Dynamics in Chronic Kidney Disease Induced by 5/6 Nephrectomy

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 349
Author(s):  
Rodrigo Prieto-Carrasco ◽  
Fernando E. García-Arroyo ◽  
Omar Emiliano Aparicio-Trejo ◽  
Pedro Rojas-Morales ◽  
Juan Carlos León-Contreras ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Mitochondrial Biogenesis ◽  
Renal Mass ◽  
Renal Damage ◽  
Peroxisome Proliferator ◽  
Progressive Reduction ◽  
Ckd Progression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitochondrial Mass ◽  
Mitochondrial Impairment

The five-sixth nephrectomy (5/6Nx) model is widely used to study the mechanisms involved in chronic kidney disease (CKD) progression. Mitochondrial impairment is a critical mechanism that favors CKD progression. However, until now, there are no temporal studies of the change in mitochondrial biogenesis and dynamics that allow determining the role of these processes in mitochondrial impairment and renal damage progression in the 5/6Nx model. In this work, we determined the changes in mitochondrial biogenesis and dynamics markers in remnant renal mass from days 2 to 28 after 5/6Nx. Our results show a progressive reduction in mitochondrial biogenesis triggered by reducing two principal regulators of mitochondrial protein expression, the peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and the peroxisome proliferator-activated receptor alpha. Furthermore, the reduction in mitochondrial biogenesis proteins strongly correlates with the increase in renal damage markers. Additionally, we found a slow and gradual change in mitochondrial dynamics from fusion to fission, favoring mitochondrial fragmentation at later stages after 5/6Nx. Together, our results suggest that 5/6Nx induces the progressive reduction in mitochondrial mass over time via the decrease in mitochondrial biogenesis factors and a slow shift from mitochondrial fission to fusion; both mechanisms favor CKD progression in the remnant renal mass.

Sirtuin 1 is involved in oleic acid-induced calf hepatocyte steatosis via alterations in lipid metabolism-related proteins

2021 ◽  
Vol 99 (10) ◽  
Author(s):  
Hongyan Ding ◽  
Yu Li ◽  
Leihong Liu ◽  
Ning Hao ◽  
Suping Zou ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mrna Abundance ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Acetyl Coa Carboxylase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lower Protein ◽  
Tag Accumulation

Abstract Sirtuin 1 (SIRT1), an NAD-dependent protein deacetylase, plays a central role in the control of lipid metabolism in nonruminants. However, the role of SIRT1 in hepatic lipid metabolism in dairy cows with fatty liver is not well known. Thus, we used isolated primary bovine hepatocytes to determine the role of SIRT1 in protecting cells against oleic acid (OA)-induced steatosis. Recombinant adenoviruses to overexpress (AD-GFP-SIRT1-E) or knockdown (AD-GFP-SIRT1-N) SIRT1 were used for transduction of hepatocytes. Calf hepatocytes isolated from five female calves (1 d old, 30 to 40 kg) were used to determine both time required and the lowest dose of OA that could induce triacylglycerol (TAG) accumulation. Analyses indicated that 0.25 mM OA for 24 h was suitable to induce TAG accumulation. In addition, OA not only led to an increase in TAG, but also upregulated mRNA and protein abundance of sterol regulatory element-binding transcription factor 1 (SREBF1) and downregulated SIRT1 and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PPARGC1A). Thus, these in vitro conditions were deemed optimal for subsequent experiments. Calf hepatocytes were cultured and incubated with OA (0.25 mM) for 24 h, followed by adenoviral AD-GFP-SIRT1-E or AD-GFP-SIRT1-N transduction for 48 h. Overexpression of SIRT1 led to greater protein and mRNA abundance of SIRT1 along with fatty acid oxidation-related genes including PPARGC1A, peroxisome proliferator-activated receptor alpha (PPARA), retinoid X receptor α (RXRA), and ratio of phospho-acetyl-CoA carboxylase alpha (p-ACACA)/total acetyl-CoA carboxylase alpha (ACACA). In contrast, it resulted in lower protein and mRNA abundance of genes related to lipid synthesis including SREBF1, fatty acid synthase (FASN), apolipoprotein E (APOE), and low-density lipoprotein receptor (LDLR). The concentration of TAG decreased due to SIRT1 overexpression. In contrast, silencing SIRT1 led to lower protein and mRNA abundance of SIRT1, PPARGC1A, PPARA, RXRA, and greater protein and mRNA abundance of SREBF1, FASN, APOE, and LDLR. Further, those responses were accompanied by greater content of cellular TAG and total cholesterol (TC). Overall, data from these in vitro studies indicated that SIRT1 is involved in the regulation of lipid metabolism in calf hepatocytes subjected to an increase in the supply of OA. Thus, it is possible that alterations in SIRT1 abundance and activity in vivo contribute to development of fatty liver in dairy cows.

Abstract 331: Recovery of Mitochondrial Bioenergetics after Hypoxia via Regulating Pyruvate Dehydrogenase Kinase and Adenosine Monophosphate-activated Kinase

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jessica M Toli ◽  
Minzhen He ◽  
Carolyn Suzuki ◽  
Maha Abdellatif
Keyword(s):  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Cardiac Myocytes ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Neonatal Rat ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mitochondrial Bioenergetics ◽  
Peroxisome Proliferator Activated Receptor

Mitochondrial quality control is critical for the survival of cardiac myocytes during stress. The purpose of this study was to examine the effect of metabolic substrates and regulators of metabolism on mitochondrial bioenergetics, as an indicator of mitochondrial quality, and how these factors might influence the recovery of the cell’s bioenergetics after hypoxia/ischemia. By monitoring oxygen consumption rates (OCR), in real-time, in live neonatal rat myocytes and human cardiac myocyte-differentiated induced pluripotent stem cells, we found that both cell types can maintain basal OCR efficiently with any metabolic substrate; however, the neonatal cells require both glucose and fatty acid, while the human adult cells require fatty acid only, for mounting maximum reserve respiratory capacity (RRC). Our data also show that subjecting cardiac myocytes to hypoxia results in a reduction of the cells’ basal OCR and oxidative phosphorylation, and exhausts the RRC, which is accompanied by an increase in pyruvate dehydrogenase kinase (Pdk) 1 and 4. Except for normalization of Pdk1 levels, there was little or no recovery of these parameters after reoxygenation. We, thus, hypothesized, that inhibition of Pdks may help recovery of the cell’s bioenergetics. Indeed, our results show that by inhibiting Pdks with dichloroacetate (DCA) before or after hypoxia, the cells’ bioenergetics, including OCR, oxidative phosphorylation, and RRC in neonatal myocytes, and RRC in the human myocytes fully recover within 24 h. On the other hand, activating AMP-activated kinase (AMPK) resulted in delayed (96 h) improvement of the cells’ RRC that was accompanied by an increase in peroxisome proliferator-activated receptor gamma, coactivator 1α (3.5x), peroxisome proliferator-activated receptor-α (2x), and mitochondrial number (2x). These results led us to conclude that compromised mitochondrial quality can be rescued through mechanisms that regulate glucose or fatty acid oxidation by either inhibiting Pdks or activating AMPK, respectively, in rodent and human myocytes.

The Effect of Aerobic Exercise on Deteriorating VO2max and Diminished Mitochondrial Biogenesis During Aging

2021 ◽  
Vol 15 (12) ◽  
pp. 3462-3466
Author(s):  
Eda Akkiz Ağaşcioğlu ◽  
Ofcan Oflaz
Keyword(s):  
Aerobic Exercise ◽  
Mitochondrial Biogenesis ◽  
Vital Capacity ◽  
Antioxidant Activities ◽  
Reduction Rate ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Physiological Level ◽  
Cellular Environment ◽  
Age Related

Aging seems to be inevitable and gradual loss of physical activity is associated with frailty and many age-related disorders. Exercise is the way of keeping a healthy life and delaying aging process. Deterioration in pulmonary vital capacity is inevitable, and mitochondrial biogenesis also diminishes with aging. Regular aerobic exercise alleviates the diminishing vital capacity while increasing mitochondrial biogenesis in aging. Peroxisome proliferator-activated receptor c coactivator 1 alpha (PGC-1a), which is the master regulator of mitochondrial biogenesis, is activated by reactive oxygen species (ROS). Exercise-induced lactate leads to formation of ROS and synthesis of nitric oxide (NO) at physiological level. PGC1a regulation by NO seems to be controversial. Over the physiological limit of ROS and NO has toxic effects in cellular environment with reduced antioxidant activities in aging. Overall, exercise seems to be beneficial option to alleviate reduction rate of vital capacity and to enhance mitochondrial biogenesis via lactate-induced ROS formation. Keywords: Aging, Exercise, Maximum oxygen consumption rate, Lungs vital capacity, Mitochondria Biogenesis.

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

Hypertension ◽  
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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