scholarly journals Further Investigation of Mitochondrial Biogenesis and Gene Expression of Key Regulators in Ascites- Susceptible and Ascites-Resistant Broiler Research Lines

2018 ◽  
Author(s):  
Khaloud Al-Zahrani ◽  
Timothy Licknack ◽  
Destiny L. Watson ◽  
Nicholas B. Anthony ◽  
Douglas D. Rhoads
Keyword(s):  
Mitochondrial Biogenesis ◽  
Copy Number ◽  
Strong Association ◽  
Predictive Marker ◽  
Breast Muscle ◽  
Resistant Line ◽  
Mtdna Copy Number ◽  
Pulmonary Hypertension Syndrome ◽  
Susceptible Line ◽  
Mrna Gene

AbstractWe have extended our previous survey of the association of mitochondrial prevalence in particular tissues with ascites susceptibility in broilers. We previously reported that in breast muscle of 22 week old susceptible line male birds had significantly higher mtDNA copy number relative to nuclear copy number (mtDNA/nucDNA), compared to resistant line male birds. The higher copy number correlated with higher expression of PPARGC1A mRNA gene. Ascites is a significant metabolic disease associated with fast-growing meat-type chickens (broilers) and is a terminal result of pulmonary hypertension syndrome. We now report the mtDNA/nucDNA ratio in lung, liver, heart, thigh, and breast of both genders at 3, and 20 weeks old. At 3 weeks the mtDNA/nucDNA ratio is significantly higher in lung, breast, and thigh for susceptible line males compared to the resistant line males. Conversely, we see the opposite for lung and breast in females. At 20 weeks of age the differences between males from the two lines is lost for lung, and thigh. Although there is a significant reduction in the mtDNA/nucDNA ratio of breast from 3 weeks to 20 weeks in the susceptible line males, the susceptible males remain higher than resistant line males for this specific tissue. We assessed relative expression of five genes known to regulate mitochondrial biogenesis for lung, thigh and breast muscle from males and females of both lines with no consistent pattern to explain the marked gender and line differences for these tissues. Our results indicate clear sex differences in mitochondrial biogenesis establishing a strong association between the mtDNA quantity in a tissue-specific manner and correlated with ascites-phenotype. We propose that mtDNA/nucDNA levels could serve as a potential predictive marker in breeding programs to reduce ascites.

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.

scholarly journals Twinkle overexpression prevents cardiac rupture after myocardial infarction by alleviating impaired mitochondrial biogenesis

2016 ◽  
Vol 311 (3) ◽  
pp. H509-H519 ◽  
Author(s):  
Takahiro Inoue ◽  
Masataka Ikeda ◽  
Tomomi Ide ◽  
Takeo Fujino ◽  
Yuka Matsuo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Mitochondrial Biogenesis ◽  
Copy Number ◽  
Cardiac Rupture ◽  
Mtdna Copy Number ◽  
Border Area ◽  
Frame Duplication ◽  
And Oxidative Stress

Cardiac rupture is a fatal complication after myocardial infarction (MI). However, the detailed mechanism underlying cardiac rupture after MI remains to be fully elucidated. In this study, we investigated the role of mitochondrial DNA (mtDNA) and mitochondria in the pathophysiology of cardiac rupture by analyzing Twinkle helicase overexpression mice (TW mice). Twinkle overexpression increased mtDNA copy number approximately twofold and ameliorated ischemic cardiomyopathy at day 28 after MI. Notably, Twinkle overexpression markedly prevented cardiac rupture and improved post-MI survival, accompanied by the suppression of MMP-2 and MMP-9 in the MI border area at day 5 after MI when cardiac rupture frequently occurs. Additionally, these cardioprotective effects of Twinkle overexpression were abolished in transgenic mice overexpressing mutant Twinkle with an in-frame duplication of amino acids 353–365, which resulted in no increases in mtDNA copy number. Furthermore, although apoptosis and oxidative stress were induced and mitochondria were damaged in the border area, these injuries were improved in TW mice. Further analysis revealed that mitochondrial biogenesis, including mtDNA copy number, transcription, and translation, was severely impaired in the border area at day 5. In contrast, Twinkle overexpression maintained mtDNA copy number and restored the impaired transcription and translation of mtDNA in the border area. These results demonstrated that Twinkle overexpression alleviated impaired mitochondrial biogenesis in the border area through maintained mtDNA copy number and thereby prevented cardiac rupture accompanied by the reduction of apoptosis and oxidative stress, and suppression of MMP activity.

scholarly journals Mitochondrial Biogenesis, Telomere Length and Cellular Senescence in Parkinson’s Disease and Lewy Body Dementia

2021 ◽  
Author(s):  
Muhammad Asghar ◽  
Amani Odeh ◽  
Ahmad Jouni Fattahi ◽  
Alexandra Edward Henriksson ◽  
Aurelie Miglar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Telomere Length ◽  
Cellular Senescence ◽  
Mitochondrial Biogenesis ◽  
Copy Number ◽  
Cellular Aging ◽  
Mtdna Copy Number

Abstract Background Progressive age is the single major risk factor for neurodegenerative diseases. Cellular aging markers during the course of Parkinson’s disease (PD) have been implicated in previous studies, however majority of these studies have investigated the association of individual cellular aging hallmarks with PD but not jointly. Method Here, we have studied the association of PD with three aging hallmarks (telomere attrition, mitochondrial dysfunction, and cellular senescence) in blood and the brain tissue. Telomere length and mitochondrial DNA ( mtDNA ) copy number was assessed by qPCR, while mitochondrial function ( PGC-1α and PGC-1β ) and expression of cyclin-dependent kinase inhibitor 2A ( CDKN2A ), cellular senescence marker was measured by RT-qPCR. Results Our results show that patients diagnosed with PD had 20% lower mitochondrial DNA copy number but 26% longer telomeres in blood compared to controls. Moreover, telomere length in blood was positively correlated with medication (Levodopa Equivalent Daily Dose). Similar results were found in brain tissue, where patients with Parkinson’s disease (PD), Parkinson dementia (PDD) and Dementia with Lewy Bodies (DLB) showed (46-95%) depleted mtDNA copy number, but (7-9%) longer telomeres compared to controls. Furthermore, when compared to controls, patients had lower mitochondrial biogenesis ( PGC-1α and PGC-1β ) and higher load of cellular senescent cells in postmortem prefrontal cortex tissue, where DLB showing the highest effect among the patient groups. Conclusion Our results show that mitochondrial dysfunction and cellular senescence but not telomere shortening is associated with PD, PDD and DLB. Our findings suggest that mitochondrial copy number and function could be used as viable biomarker in blood as an early indicator for the risk of neurodegenerative diseases.

scholarly journals Urea Memory: Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 410 ◽  
Author(s):  
Maria d’Apolito ◽  
Anna Colia ◽  
Enrica Manca ◽  
Massimo Pettoello-Mantovani ◽  
Michele Sacco ◽  
...  
Keyword(s):  
Fusion Proteins ◽  
Copy Number ◽  
Electron Transport Chain ◽  
Mitochondrial Fission ◽  
Functional Decline ◽  
Cell Types ◽  
Mtdna Copy Number ◽  
Mitochondrial Ros ◽  
Transport Chain ◽  
Arterial Endothelial Cells

Urea at post-dialysis levels induces increased ROS in a number of cell types. The aim of this study was to determine whether urea-induced production of ROS remains elevated after urea is no longer present, and, if it does, to characterize its origin and effects. Human arterial endothelial cells were incubated with 20 mM urea for two days, and then cells were incubated for an additional two days in medium alone. Maximal ROS levels induced by initial urea continued at the same level despite urea being absent. These effects were prevented by either MnSOD expression or by Nox1/4 inhibition with GKT13781. Sustained urea-induced ROS caused a persistent reduction in mtDNA copy number and electron transport chain transcripts, a reduction in transcription of mitochondrial fusion proteins, an increase in mitochondrial fission proteins, and persistent expression of endothelial inflammatory markers. The SOD-catalase mimetic MnTBAP reversed each of these. These results suggest that persistent increases in ROS after cells are no long exposed to urea may play a major role in continued kidney damage and functional decline despite reduction of urea levels after dialysis.

scholarly journals mtDNA in the Pathogenesis of Cardiovascular Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Lili Wang ◽  
Qianhui Zhang ◽  
Kexin Yuan ◽  
Jing Yuan
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Heart Diseases ◽  
Mtdna Copy Number ◽  
Cardiac Inflammation ◽  
Ischemic Heart Diseases ◽  
Metabolic Functions ◽  
Underlying Mechanisms

The incidence rate of cardiovascular disease (CVD) has been increasing year by year and has become the main cause for the increase of mortality. Mitochondrial DNA (mtDNA) plays a crucial role in the pathogenesis of CVD, especially in heart failure and ischemic heart diseases. With the deepening of research, more and more evidence showed that mtDNA is related to the occurrence and development of CVD. Current studies mainly focus on how mtDNA copy number, an indirect biomarker of mitochondrial function, contributes to CVD and its underlying mechanisms including mtDNA autophagy, the effect of mtDNA on cardiac inflammation, and related metabolic functions. However, no relevant studies have been conducted yet. In this paper, we combed the current research status of the mechanism related to the influence of mtDNA on the occurrence, development, and prognosis of CVD, so as to find whether these mechanisms have something in common, or is there a correlation between each mechanism for the development of CVD?

scholarly journals Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters

2021 ◽  
Vol 12 ◽  
Author(s):  
Jonghyuk Park ◽  
Jimmy Kim ◽  
Toshio Mikami
Keyword(s):  
Blood Lactate ◽  
Mitochondrial Biogenesis ◽  
High Intensity ◽  
Lactate Concentration ◽  
High Intensity Exercise ◽  
Mtdna Copy Number ◽  
Single Bout ◽  
Extracellular Lactate ◽  
Exercise Induced ◽  
The Brain

Regular exercise training induces mitochondrial biogenesis in the brain via activation of peroxisome proliferator-activated receptor gamma-coactivator 1α (PGC-1α). However, it remains unclear whether a single bout of exercise would increase mitochondrial biogenesis in the brain. Therefore, we first investigated whether mitochondrial biogenesis in the hippocampus is affected by a single bout of exercise in mice. A single bout of high-intensity exercise, but not low- or moderate-intensity, increased hippocampal PGC-1α mRNA and mitochondrial DNA (mtDNA) copy number at 12 and 48h. These results depended on exercise intensity, and blood lactate levels observed immediately after exercise. As lactate induces mitochondrial biogenesis in the brain, we examined the effects of acute lactate administration on blood and hippocampal extracellular lactate concentration by in vivo microdialysis. Intraperitoneal (I.P.) lactate injection increased hippocampal extracellular lactate concentration to the same as blood lactate level, promoting PGC-1α mRNA expression in the hippocampus. However, this was suppressed by administering UK5099, a lactate transporter inhibitor, before lactate injection. I.P. UK5099 administration did not affect running performance and blood lactate concentration immediately after exercise but attenuated exercise-induced hippocampal PGC-1α mRNA and mtDNA copy number. In addition, hippocampal monocarboxylate transporters (MCT)1, MCT2, and brain-derived neurotrophic factor (BDNF) mRNA expression, except MCT4, also increased after high-intensity exercise, which was abolished by UK5099 administration. Further, injection of 1,4-dideoxy-1,4-imino-D-arabinitol (glycogen phosphorylase inhibitor) into the hippocampus before high-intensity exercise suppressed glycogen consumption during exercise, but hippocampal lactate, PGC-1α, MCT1, and MCT2 mRNA concentrations were not altered after exercise. These results indicate that the increased blood lactate released from skeletal muscle may induce hippocampal mitochondrial biogenesis and BDNF expression by inducing MCT expression in mice, especially during short-term high-intensity exercise. Thus, a single bout of exercise above the lactate threshold could provide an effective strategy for increasing mitochondrial biogenesis in the hippocampus.

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