scholarly journals Mitochondrial Dysfunction in Metabolic Disease

2012 ◽  
Vol 4 (3) ◽  
pp. 119
Author(s):  
Anna Meiliana ◽  
Andi Wijaya
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Stress Responses ◽  
Metabolic Diseases ◽  
Respiratory Enzymes ◽  
Mitochondrial Oxidative Stress ◽  
Cancer Pathways ◽  
Wide Range ◽  
Key Factor

BACKGROUND: Mitochondrial function and behavior are central to the physiology of humans and, consequently, "mitochondrial dysfunction" has been implicated in a wide range of disease.CONTENT: Mitochondrial ROS might attack various mitochondrial constituents, causing mitochondrial DNA mutations and oxidative damage to respiratory enzymes. A defect in mitochondrial respiratory enzymes would increase mitochondrial production of ROS, causing further mitochondrial damage and dysfunction. Mitochondrial dysfunction is associated with diseases, such as neurodegenerative disorders, cardiomyopathies, metabolic syndrome, obesity, and cancer. Pathways that improve mitochondrial function, attenuate mitochondrial oxidative stress, and regulate mitochondrial biogenesis have recently emerged as potential therapeutic targets.SUMMARY: Mitochondria perform diverse yet interconnected functions, produce ATP and many biosynthetic intermediates while also contribute to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network that is intimately integrated with other cellular compartments. It is therefore not suprising that mitochondrial dysfunction has emerged as a key factor in a myriad of diseases, including neurodegenerative, cancer, and metabolic disorders. Interventions that modulate processes involved in regulation of mitochondrial turnover, with calorie restriction and induction of mitochondrial biogenesis, are of particular interest.KEYWORDS: mitochondrial biogenesis, mitochondrial dysfunction, reactive oxygen species (ROS), metabolic diseases

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 < 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 < 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.

Abstract P608: Obesity Induced Hypertension Exacerbated Through Upregulation Of Renal Naci Cotransporter, Reversed By Increasing Pgc-1α-ho-1 Gene Expression To Restore Mitochondrial Function

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
David Bamshad ◽  
Jian Cao ◽  
Joseph Schragenheim ◽  
Charles T Stier ◽  
Nader G Abraham
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Sodium Excretion ◽  
Leptin Receptor ◽  
Insulin Receptors ◽  
Urinary Sodium Excretion ◽  
Induced Hypertension ◽  
Group A ◽  
Group B

Introduction: Hypertension caused by chronic obesity as a result of high calorie food intake or in leptin receptor deficient db/db mice may be linked to mitochondrial dysfunction. Previously we and others have shown that an epoxyeicosatrienoic acid agonist (EET-A), reduced adiposity and ROS resulting in normalization of BP by unknown mechanisms. We hypothesize that EET-A will attenuate BP by restoring mitochondrial function through increasing the PGC-1α-HO-1 axis and increasing urinary sodium excretion by downregulating NCC channels. Methods: Db/db mice at 16-wks of age were divided into 3 treatment groups and for an additional 16-wks received: A) control, B) EET-A 1.5mg/100g BW i.p. 2x/week and C) EET-A and lentiviral (Ln)- PGC-1α shRNA (to suppress PGC-1α protein). Oxygen consumption (VO 2 ), visceral fat and blood glucose were determined. Additionally, renal tissues were harvested to measure the type 2 Na-K-Cl cotransporters (NKCC2), epithelial Na channels- (ENaC), NaCl cotransporters (NCC), PGC-1α, HO-1, insulin receptors, and mitochondrial biogenesis markers. Results: At the conclusion of 32 weeks: Group A, developed hypertension and presented with decreased urinary Na excretion, decreased VO 2 , decreased downstream PGC-1α signaling, and mitochondrial dysfunction. There were increased levels of NCCs but not of NKCC2s or ENaCs. Renal PGC-1α, HO-1, pAMPK, and mitochondrial fusion protein Mfn 1/2, and Opa1 were decreased, p<0.05. Group B, exhibited restoration of renal levels of PGC-1α, HO-1, pAMPK, and mitochondrial biogenesis proteins Mfn 1/2 and Opa1. NCC expression was reduced and was associated with an increase in urinary Na excretion; (p<0.05). The beneficial effect of EET-A observed in group B was suppressed in group C using Ln- PGC-1α shRNA which suppressed PGC-1α expression in renal tissue > 50% and was accompanied by the onset of even more severe suppression of urinary Na excretion than in Group A. Conclusion: Treatment of obese mice with EET-agonists leads to the recruitment of PGC-1α-HO-1 which enhances mitochondrial function and induces the downregulation of NCC channels and increased sodium excretion. EET may serve as a powerful therapeutic agent for the treatment of obesity induced hypertension.

scholarly journals Mitochondrial Quality Control Mechanisms and the PHB (Prohibitin) Complex

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 238 ◽  
Author(s):  
Blanca Hernando-Rodríguez ◽  
Marta Artal-Sanz
Keyword(s):  
Quality Control ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Stress Responses ◽  
Membrane Lipids ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Gene ◽  
Control Mechanisms ◽  
Mitochondrial Homeostasis ◽  
Mitochondrial Functions

Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress, and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the oxidative phosphorylation (OXPHOS) system for ATP production. It requires, in addition, the import of a large number of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue, and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPRmt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial prohibitin (PHB) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease

2015 ◽  
Vol 129 (7) ◽  
pp. 589-599 ◽  
Author(s):  
Joaquin Perez-Schindler ◽  
Andrew Philp
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Nuclear Receptors ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Muscle Metabolism ◽  
Cellular Level ◽  
Expression Of Genes

Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease.

scholarly journals Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and enhanced mitochondrial biogenesis in human fibroblasts

2020 ◽  
Author(s):  
Yasuhiro Takenaka ◽  
Ikuo Inoue ◽  
Takanari Nakano ◽  
Masaaki Ikeda ◽  
Yoshihiko Kakinuma
Keyword(s):  
Antioxidant Enzymes ◽  
Drug Treatment ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mitochondrial Biogenesis ◽  
Stress Responses ◽  
Time Course ◽  
Human Fibroblasts ◽  
Early Period ◽  
Functional Changes

AbstractProteolytic activities decline with age, resulting in the accumulation of aggregated proteins in aged organisms. To investigate how disturbance of proteostasis causes cellular senescence in proliferating cells, we developed a stress-induced premature senescence (SIPS) model, in which normal human fibroblast MRC-5 cells were treated with either the proteasome inhibitor MG132 or V-ATPase inhibitor bafilomycin A1 (BAFA1). After 5 days of drug treatment, cells showed morphological and functional changes associated with aging along with DNA damage response. Time-course studies revealed significant increase in intracellular and mitochondrial reactive oxygen species (ROS) during and after drug treatment. We also found temporal downregulation of mitochondrial membrane potential during drug treatment, followed by an increase in mitochondrial mass, especially after drug treatment. Notable upregulation of PGC-1α and TFAM proteins confirmed enhanced mitochondrial biogenesis. Furthermore, the protein levels of SOD2 and GPx4, mitochondrial antioxidant enzymes, in the mitochondrial fraction were specifically reduced on day 1 of the treatment. Co-treatment with rapamycin along with MG132 or BAFA1 partially attenuated induction of SIPS by suppressing generation of excess ROS and mitochondrial biogenesis. In conclusion, the present study revealed that disturbance of proteostasis by the inhibitors changes the distribution of nuclear-encoded mitochondrial antioxidant enzymes at an early period of the treatment, which induces mitochondrial ROS and temporal mitochondrial dysfunction. ROS in turn activates stress responses pathways, followed by PGC-1α-mediated mitochondrial biogenesis. Hence, the excessive ROS continuously generated by increased mitochondria can cause deleterious damage to nuclear DNA, cell cycle arrest, and eventual cellular senescence.

scholarly journals Effects of (−)-epicatechin on mitochondria

2020 ◽  
Vol 79 (1) ◽  
pp. 25-41
Author(s):  
Frédéric N Daussin ◽  
Elsa Heyman ◽  
Yan Burelle
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Genetic Disorders ◽  
Natural Compounds ◽  
Human Diseases ◽  
Therapeutic Applications ◽  
Effective Strategies

Abstract Mitochondrial dysfunction is observed in a broad range of human diseases, including rare genetic disorders and complex acquired pathologies. For this reason, there is increasing interest in identifying safe and effective strategies to mitigate mitochondrial impairments. Natural compounds are widely used for multiple indications, and their broad healing properties suggest that several may improve mitochondrial function. This review focuses on (−)-epicatechin, a monomeric flavanol, and its effects on mitochondria. The review summarizes the available data on the effects of acute and chronic (−)-epicatechin supplementation on mitochondrial function, outlines the potential mechanisms involved in mitochondrial biogenesis induced by (−)-epicatechin supplementation and discusses some future therapeutic applications.

Naringenin improves mitochondrial function and reduces cardiac damage following ischemia-reperfusion injury: the role of the AMPK-SIRT3 signaling pathway

2019 ◽  
Vol 10 (5) ◽  
pp. 2752-2765 ◽  
Author(s):  
Li-Ming Yu ◽  
Xue Dong ◽  
Xiao-Dong Xue ◽  
Jian Zhang ◽  
Zhi Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reperfusion Injury ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Damage ◽  
Mitochondrial Oxidative Stress ◽  
Stress Damage

Naringenin directly inhibits mitochondrial oxidative stress damage and preserves mitochondrial biogenesisviaAMPK-SIRT3 signaling, thus attenuating MI/R injury.

Mitochondrial dysfunction is associated with long-term cognitive impairment in an animal sepsis model

2019 ◽  
Vol 133 (18) ◽  
pp. 1993-2004 ◽  
Author(s):  
Andressa Manfredini ◽  
Larissa Constantino ◽  
Milton Castro Pinto ◽  
Monique Michels ◽  
Henrique Burger ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Cecal Ligation ◽  
Inhibitory Avoidance ◽  
Sepsis Survivors

Abstract Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis. Methods: Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7–9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function. Results: Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors. Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment.

scholarly journals Natural killer cells contribute to mitochondrial dysfunction in response to placental ischemia in reduced uterine perfusion pressure rats

2019 ◽  
Vol 316 (5) ◽  
pp. R441-R447 ◽  
Author(s):  
Venkata Ramana Vaka ◽  
Kristen M. McMaster ◽  
Denise C. Cornelius ◽  
Tarek Ibrahim ◽  
Aswathi Jayaram ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Natural Killer ◽  
Mitochondrial Function ◽  
Perfusion Pressure ◽  
Nk Cell ◽  
Cell Depletion ◽  
Mitochondrial Oxidative Stress ◽  
Uterine Perfusion ◽  
Placental Ischemia

Preeclampsia (PE) is characterized by new-onset hypertension during pregnancy and is associated with immune activation and placental oxidative stress. Mitochondrial dysfunction is a major source of oxidative stress and may play a role in the pathology of PE. We (Vaka VR, et al. Hypertension 72: 703–711, 2018. doi: 10.1161/HYPERTENSIONAHA.118.11290 .) have previously shown that placental ischemia is associated with mitochondrial oxidative stress in the reduced uterine perfusion pressure (RUPP) model of PE. Furthermore, we have also shown that placental ischemia induces natural killer (NK) cell activation in RUPP. Thus, we hypothesize that NK cell depletion could improve mitochondrial function associated with hypertension in the RUPP rat model of PE. Pregnant Sprague-Dawley rats were divided into three groups: normal pregnant (NP), RUPP, and RUPP+NK cell depletion rats (RUPP+NKD). On gestational day ( GD) 14, RUPP surgery was performed, and NK cells were depleted by administering anti-asialo GM1 antibodies (3.5 µg/100 µl ip) on GD15 and GD17. On GD19, mean arterial pressure (MAP) was measured, and placental mitochondria were isolated and used for mitochondrial assays. MAP was elevated in RUPP versus NP rats (119 ± 1 vs.104 ± 2 mmHg, P = 0.0004) and was normalized in RUPP+NKD rats (107 ± 2 mmHg, P = 0.002). Reduced complex IV activity and state 3 respiration rate were improved in RUPP+NKD rats. Human umbilical vein endothelial cells treated with RUPP+NKD serum restored respiration with reduced mitochondrial reactive oxygen species (ROS). The restored placental or endothelial mitochondrial function along with attenuated endothelial cell mitochondrial ROS with NK cell depletion indicate an important role of NK cells in mediating mitochondrial oxidative stress in the pathology of PE.

scholarly journals Sarcopenia, Aging and Prospective Interventional Strategies

2019 ◽  
Vol 25 (40) ◽  
pp. 5588-5596 ◽  
Author(s):  
Tyler B. Waltz ◽  
Elayne M. Fivenson ◽  
Marya Morevati ◽  
Chuanhao Li ◽  
Kevin G. Becker ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Human Health ◽  
Healthcare System ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Stress Resistance ◽  
Cellular Stress ◽  
Naturally Occurring ◽  
Age Related ◽  
Urolithin A

Sarcopenia, or age-related muscle decline, occurs in most organisms and burdens both human health and the healthcare system. As our population ages, additional options for treating sarcopenia are needed. Mitochondrial dysfunction is implicated in the onset of sarcopenia, so therapies directed at improving mitochondrial function in muscle should be considered. Many naturally-occurring compounds, derived from commonly consumed foods, possess anti-sarcopenic effects, such asnicotinamide riboside, tomatidine, and Urolithin A. These naturally-occurring compounds can improve mitochondrial health and efficiency by modulating mitochondrial biogenesis, cellular stress resistance, or mitophagy. Further research should assess whether compounds that improve mitochondrial health can attenuate sarcopenia in humans.

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