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.

scholarly journals Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

2021 ◽  
Vol 22 (15) ◽  
pp. 8333
Author(s):  
Carsten Esselun ◽  
Ellen Theyssen ◽  
Gunter P. Eckert
Keyword(s):  
Alzheimer Disease ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Neuroprotective Activity ◽  
Peroxisome Proliferator ◽  
Cellular Model ◽  
Qrt Pcr ◽  
Expression Of Genes ◽  
Age Related ◽  
Urolithin A

(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA’s effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA’s effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis.

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 Age-Associated Mitochondrial Dysfunction Accelerates Atherogenesis

2020 ◽  
Vol 126 (3) ◽  
pp. 298-314 ◽  
Author(s):  
Daniel J. Tyrrell ◽  
Muriel G. Blin ◽  
Jianrui Song ◽  
Sherri C. Wood ◽  
Min Zhang ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Tissue ◽  
Wild Type ◽  
Il Interleukin ◽  
Age Related ◽  
Density Lipoprotein Receptor ◽  
Young Mice

Rationale: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. Objective: To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. Methods and Results: We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Conclusions: Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.

Urolithin A protects dopaminergic neurons in experimental models of Parkinson’s disease by promoting mitochondrial biogenesis through SIRT1/PGC-1α signaling pathway

2021 ◽  
Author(s):  
Jia Liu ◽  
Jingjing Jiang ◽  
Jingru Qiu ◽  
Liyan Wang ◽  
Jing Zhuo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathway ◽  
Mitochondrial Biogenesis ◽  
Dopaminergic Neurons ◽  
Therapeutic Strategies ◽  
Experimental Models ◽  
Urolithin A

Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of PD. Recent reports have...

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.

scholarly journals Water-soluble CoQ10 as A Promising Anti-aging Agent for Neurological Dysfunction in Brain Mitochondria

Antioxidants ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 61 ◽  
Author(s):  
Mayumi Takahashi ◽  
Kazuhide Takahashi
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Coenzyme Q ◽  
Brain Mitochondria ◽  
Water Soluble ◽  
Neurological Dysfunction ◽  
Complex Iv ◽  
Age Related ◽  
Motor Activities ◽  
Water Solubilization

Mitochondrial function has been closely associated with normal aging and age-related diseases. Age-associated declines in mitochondrial function, such as changes in oxygen consumption rate, cytochrome c oxidase activity of complex IV, and mitochondrial coenzyme Q (CoQ) levels, begin as early as 12 to 15 months of age in male mouse brains. Brain mitochondrial dysfunction is accompanied by increased accumulation of phosphorylated α-synuclein in the motor cortex and impairment of motor activities, which are similar characteristics of Parkinson’s disease. However, these age-associated defects are completely rescued by the administration of exogenous CoQ10 to middle-aged mice via its water solubilization by emulsification in drinking water. Further efforts to develop strategies to enhance the biological availability of CoQ10 to successfully ameliorate age-related brain mitochondrial dysfunction or neurodegenerative disorders may provide a promising anti-aging agent.

scholarly journals Long-term treated HIV infection is associated with platelet mitochondrial dysfunction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wouter A. van der Heijden ◽  
Lisa van de Wijer ◽  
Martin Jaeger ◽  
Karin Grintjes ◽  
Mihai G. Netea ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ex Vivo ◽  
Platelet Reactivity ◽  
Inflammatory Marker ◽  
People Living With Hiv ◽  
Normal Platelet ◽  
Function Tests ◽  
Age Related

AbstractHIV infection and antiretroviral therapy have been linked to mitochondrial dysfunction. The role of platelet mitochondrial dysfunction in thrombosis, immunoregulation and age-related diseases is increasingly appreciated. Here, we studied platelet mitochondrial DNA content (mtDNApl) and mitochondrial function in people living with HIV (PLHIV) and related this to platelet function. In a cohort of 208 treated PLHIV and 56 uninfected controls, mtDNApl was quantified, as well as platelet activation, platelet agonist-induced reactivity and inflammation by circulating factors and flow cytometry. In a subgroup of participants, the metabolic activity of platelets was further studied by mitochondrial function tests and the Seahorse Flux Analyzer. PLHIV had significantly lower mtDNApl compared to controls (8.5 copies/platelet (IQR: 7.0–10.7) vs. 12.2 copies/platelet (IQR: 9.5–16.6); p < 0.001), also after correction for age, sex and BMI. Prior zidovudine-use (n = 46) was associated with a trend for lower mtDNApl. PLHIV also had reduced ex vivo platelet reactivity and mean platelet volume compared to controls. MtDNApl correlated positively with both platelet parameters and correlated negatively with inflammatory marker sCD163. Mitochondrial function tests in a subgroup of participants confirmed the presence of platelet mitochondrial respiration defects. Platelet mitochondrial function is disturbed in PLHIV, which may contribute to platelet dysfunction and subsequent complications. Interventions targeting the preservation of normal platelet mitochondrial function may ultimately prove beneficial for PLHIV.

scholarly journals Impact of Silibinin A on Bioenergetics in PC12APPsw Cells and Mitochondrial Membrane Properties in Murine Brain Mitochondria

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1520
Author(s):  
Carsten Esselun ◽  
Bastian Bruns ◽  
Stephanie Hagl ◽  
Rekha Grewal ◽  
Gunter P. Eckert
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Brain Mitochondria ◽  
Membrane Properties ◽  
Protective Effects ◽  
Positive Effects ◽  
Atp Levels ◽  
Age Related ◽  
Murine Brain

Introduction: Age-related multifactorial diseases, such as the neurodegenerative Alzheimer’s disease (AD), still remain a challenge to today’s society. One mechanism associated with AD and aging in general is mitochondrial dysfunction (MD). Increasing MD is suggested to trigger other pathological processes commonly associated with neurodegenerative diseases. Silibinin A (SIL) is the main bioactive compound of the Silymarin extract from the Mediterranean plant Silybum marianum (L.) (GAERTN/Compositae). It is readily available as a herbal drug and well established in the treatment of liver diseases as a potent radical scavenger reducing lipid peroxidation and stabilize membrane properties. Recent data suggest that SIL might also act on neurological changes related to MD. Methods: PC12APPsw cells produce low levels of human Aβ and thus act as a cellular model of early AD showing changed mitochondrial function. We investigated whether SIL could affect mitochondrial function by measuring ATP, MMP, as well as respiration, mitochondrial mass, cellular ROS and lactate/pyruvate concentrations. Furthermore, we investigated its effects on the mitochondrial membrane parameters of swelling and fluidity in mitochondria isolated from the brains of mice. Results: In PC12APPsw cells, SIL exhibits strong protective effects by rescuing MMP and ATP levels from SNP-induced mitochondrial damage and improving basal ATP levels. However, SIL did not affect mitochondrial respiration and mitochondrial content. SIL significantly reduced cellular ROS and pyruvate concentrations. Incubation of murine brain mitochondria with SIL significantly reduces Ca2+ induced swelling and improves membrane fluidity. Conclusions: Although OXPHOS activity was unaffected at this early stage of a developing mitochondrial dysfunction, SIL showed protective effects on MMP, ATP- after SNP-insult and ROS-levels in APPsw-transfected PC12 cells. Results from experiments with isolated mitochondria imply that positive effects possibly result from an interaction of SIL with mitochondrial membranes and/or its antioxidant activity. Thus, SIL might be a promising compound to improve cellular health when changes to mitochondrial function occur.

Mitochondria and Hematologic Disorders.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-3-SCI-3
Author(s):  
Jeff S. Friedman
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Conflicts Of Interest ◽  
Single Cells ◽  
Disease Process ◽  
Dna Lesions ◽  
Special Relationship ◽  
Hematopoietic Stem ◽  
Age Related

Abstract Abstract SCI-3 Mitochondria have a special relationship with the erythroid lineage. Although RBC are devoid of mitochondria, during RBC development the mitochondria is the site of multiple steps in heme biosynthesis, and is essential for proper utilization of iron. As evidence of this special relationship, multiple mutations in both mitochondrial DNA (hereditary and acquired) and in nuclear genes encoding mitochondrial localized proteins (hereditary) result in sideroblastic anemia—where the hallmark pathologic lesion is intramitochondrial iron accumulation in erythroid progenitors. The erythroid-lineage specific readout of these mitochondrial genetic lesions raises the possibility that mitochondrial dysfunction is a contributor to anemia in other contexts as well. In this view, red cell development can be considered an early warning system for mitochondrial dysfunction in hematopoiesis. A focus of our laboratory is to investigate how increased mitochondrial-derived reactive oxygen species affect hematopoietic development. Gene expression and proteomic analyses of erythroblasts demonstrate that mitochondrial biogenesis during erythroid development is inhibited by oxidant stress. Transcriptional control of mitochondrial biogenesis in erythroid cells involves induction of the distinct transcriptional coactivator PRC1—perhaps helping to explain the erythroid specificity of phenotypes noted above. As has been elegantly demonstrated by Wallace and others, mitochondrial dysfunction is an important determinant of age-related decline in functional capacity of many tissues. This decline in function is accompanied by an increase in mitochondrial DNA mutations—both point mutations and deletions found primarily in post-mitotic cells. Modeling of this process through creation of mice with an error prone mtDNA polymerase accelerates the appearance of age-related tissue changes—including the development of anemia. Transplantation of murine hematopoietic stem cells harboring a large deletion of mtDNA also leads to anemia in reconstituted animals. Are these findings relevant for age-related hematologic abnormalities in people—and if so, for what disorders? There is considerable epidemiologic evidence indicating an increase in the frequency of anemia in the elderly, peaking at a prevalence of greater than 20% for individuals in their 80's. Approximately 1/3 of these elderly anemic cases are idiopathic—that is, no underlying disease process is identified. In studying this group with idiopathic anemia, we have investigated a number of hypotheses including the possibility of mitochondrial dysfunction. To date we have found altered mitochondrial DNA content and a higher mutation frequency in mtDNA isolated from peripheral blood cells when comparing anemic versus age/sex matched controls. However, these studies are correlative, and do not prove causality. Proving a direct role for specific acquired mitochondrial DNA lesions in development of anemia, myelodysplasia or hematologic malignancy remains a technical challenge because of the difficulty in introducing specific mutant mtDNA's into relevant cells or tissues. The development of more facile methods for evaluation of mitochondria in few or even single cells promises to expand our understanding of how mitochondrial functional changes impact diverse hematopoietic cells, in addition to the erythroid lineage effects highlighted above. Disclosures No relevant conflicts of interest to declare.

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