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 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.

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.

Optic atrophy 1 mediates coenzyme Q-responsive regulation of respiratory complex IV activity in brain mitochondria

2017 ◽  
Vol 98 ◽  
pp. 217-223 ◽  
Author(s):  
Kazuhide Takahashi ◽  
Ikuroh Ohsawa ◽  
Takuji Shirasawa ◽  
Mayumi Takahashi
Keyword(s):  
Optic Atrophy ◽  
Coenzyme Q ◽  
Brain Mitochondria ◽  
Complex Iv ◽  
Respiratory Complex ◽  
Responsive Regulation

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.

Aging-Related Increase of cGMP Disrupts Mitochondrial Homeostasis in Leydig Cells

2020 ◽  
Author(s):  
Srdjan J Sokanovic ◽  
Aleksandar Z Baburski ◽  
Zvezdana Kojic ◽  
Marija L J Medar ◽  
Silvana A Andric ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Leydig Cells ◽  
Pde5 Inhibition ◽  
Testosterone Production ◽  
Age Related ◽  
Cgmp Signaling ◽  
Old Rats

Abstract Since mitochondria play an essential role in the testosterone biosynthesis, serve as power centers and are a source of oxidative stress, a possible mitochondrial dysfunction could be connected with decreased activity of Leydig cells and lowered testosterone production during aging. Here we chronologically analyzed age-related alterations of mitochondrial function in Leydig cells correlated by the progressive rise of cGMP signaling and with respect to testosterone synthesis. To target cGMP signaling in Leydig cells, acute or long-term in vivo or ex vivo treatments with sildenafil (phosphodiesterase 5 [PDE5] inhibitor) were performed. Aging-related accumulation of cGMP in the Leydig cells is associated with mitochondrial dysfunction illustrated by reduced ATP and steroid production, lowered O2 consumption, increased mitochondrial abundance and mtDNA copies number, decreased expression of genes that regulate mitochondrial biogenesis (Ppargc1a/PGC1a-Tfam-Nrf1/NRF1), mitophagy (Pink1), fusion (Mfn1, Opa1), and increased Nrf2/NRF2. Acute in vivo PDE5 inhibition overaccumulated cGMP and stimulated testosterone but reduced ATP production in Leydig cells from adult, middle-aged, and old rats. The increased ATP/O ratio observed in cells from old compared to adult rats was diminished after stimulation of cGMP signaling. Opposite, long-term PDE5 inhibition decreased cGMP signaling and improved mitochondrial function/dynamics in Leydig cells from old rats. Mitochondrial abundance in Leydig cells decreased while ATP levels increased. Chronic treatment elevated Tfam, Nrf1, Nrf2, Opa1, Mfn1, Drp1, and normalized Pink1 expression. Altogether, long-term PDE5 inhibition prevented age-related NO and cGMP elevation, improved mitochondrial dynamics/function, and testosterone production. The results pointed on cGMP signaling in Leydig cells as a target for pharmacological manipulation of aging-associated changes in mitochondrial function and testosterone production.

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 Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

2021 ◽  
Author(s):  
Robert V Musci ◽  
Kendra M Andrie ◽  
Maureen A Walsh ◽  
Zackary J Valenti ◽  
Maryam F Afzali ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Guinea Pigs ◽  
Muscle Protein ◽  
System Capacity ◽  
Related Factor ◽  
Age Related ◽  
Nrf2 Activator

Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze™ open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

Mitochondrial decline and chronic conditions of older adults

2017 ◽  
pp. 337-344
Author(s):  
Emanuele Marzetti ◽  
Francesco Landi ◽  
Francesca Martini ◽  
Christiaan Leeuwenburgh ◽  
Riccardo Calvani
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Functional Decline ◽  
Causative Factor ◽  
Common Denominator ◽  
Cellular Viability ◽  
Major Mechanism ◽  
Mtdna Mutations ◽  
Age Related

Ageing involves a progressive deterioration of physiological integrity which leads to increased vulnerability to stressors and multisystemic functional decline. Mitochondrial dysfunction is increasingly recognized as a common denominator of ageing and an important causative factor for major age-related conditions. Mitochondrial function becomes perturbed by age-associated accumulation of mtDNA mutations, altered mitochondriogenesis and dynamics, and abnormal regulation of mitophagy. These alterations result in diminished bioenergetic efficacy, enhanced oxidative stress, and eventually loss of cellular viability. This series of events is proposed to be a major mechanism in the ageing process and the development of chronic diseases. This chapter provides an overview on the mechanisms believed to underlie the loss of mitochondrial function with ageing. Special attention is paid to the consequences of mitochondrial dysfunction in postmitotic tissues (i.e. heart, skeletal muscle, and central nervous system), where mitochondrial damage is proposed to be responsible for the appearance of age- and disease-associated phenotypes.

scholarly journals Mitochondrial Dysfunction Increases Arrhythmic Triggers and Substrates; Potential Anti-arrhythmic Pharmacological Targets

2021 ◽  
Vol 8 ◽  
Author(s):  
Khalil Saadeh ◽  
Ibrahim Talal Fazmin
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Ionic Currents ◽  
Pharmacological Interventions ◽  
Age Related ◽  
Pharmacological Targets ◽  
Cellular Ca ◽  
Sodium And Potassium

Incidence of cardiac arrhythmias increases significantly with age. In order to effectively stratify arrhythmic risk in the aging population it is crucial to elucidate the relevant underlying molecular mechanisms. The changes underlying age-related electrophysiological disruption appear to be closely associated with mitochondrial dysfunction. Thus, the present review examines the mechanisms by which age-related mitochondrial dysfunction promotes arrhythmic triggers and substrate. Namely, via alterations in plasmalemmal ionic currents (both sodium and potassium), gap junctions, cellular Ca2+ homeostasis, and cardiac fibrosis. Stratification of patients' mitochondrial function status permits application of appropriate anti-arrhythmic therapies. Here, we discuss novel potential anti-arrhythmic pharmacological interventions that specifically target upstream mitochondrial function and hence ameliorates the need for therapies targeting downstream changes which have constituted traditional antiarrhythmic therapy.

Citrate Synthase Activity Is Increased In Children With Sickle Cell Disease (SCD) On Hydroxyurea (HU) Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4690-4690
Author(s):  
Claudia R. Morris ◽  
Cornelia Latronica ◽  
Frans A Kuypers ◽  
Howard Rosenfeld ◽  
Sandra K Larkin ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Matrix Protein ◽  
Cell Function ◽  
Citrate Synthase ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Small Sample ◽  
Complex Iv ◽  
Mitochondrial Number

Background Mitochondrial dysfunction is associated with abnormal cell function, oxidative stress and cell death. A progressive impairment of mitochondrial function and/or increased oxidative damage likely contribute to the pathophysiology of SCD, however little is known about bioenergetics in SCD. While previous work demonstrated mitochondrial dysfunction in the platelets of adult patients with SCD characterized by deficient complex IV and V activity which was associated with hemolysis, no data has yet been described in children with SCD. Objective To initiate investigation into mitochondrial function in children with SCD. Methods Children with a diagnosis of SCD requiring parenteral opioids for vaso-occlusive pain episodes (VOE) were prospectively enrolled within 24 hours of presentation to an urban emergency department (ED). Blood was obtained for biomarkers of hemolytic rate, and estimated pulmonary pressures were noninvasively measured by a point-of-care Doppler echocardiography (echo). Platelet rich plasma was isolated from patient whole blood by differential centrifugation and flash frozen for mitochondrial studies. The activities of Complexes V and IV were measured since these enzymes are the sites of oxygen consumption (Cx IV) and ATP production (CxV). The activity of citrate synthase, a mitochondrial matrix protein, was also determined as an indicator of mitochondrial number. Results 11 children with SCD seen in the ED or admitted for VOE were included in this pilot study. Mean age was 17±3 years (range: 9-21 years), 64% were male, and 45.5% had HbSS, 45.5% HbSC and 9% HbSbThal. Mean Hb was 9.9±2 g/dL, reticulocyte (retic) count was 7.6±5%, and 45.5% were on HU. Mean tricuspid regurgitant jet velocity (TRV) = 2.0±0.4 m/s. Of interest patients on HU had significantly higher citrate synthase activity (Figure 1), although Complex IV and V activities were similar in both groups. Citrate synthase activity inversely correlated with TRV (r=-0.63, p=0.04). Similar to the previously reported adult data, complex IV activity inversely correlated with retic count (R2=0.27), although not reaching statistical significance, likely due to small sample size. No difference in mitochondrial studies were found when HbSS patients were compared to those with HbSC. Conclusions These data suggest mitochondrial dysfunction and potentially decreased mitochondrial number in SCD children with increased hemolytic rate (TRV). Further, the greater citrate synthase activity in platelets of patients with SCD on HU compared to those not treated with HU may be indicative of increased mitochondrial number with HU therapy. These observations have never been previously described, and may suggest a novel mechanism of action for HU warranting further study. Disclosures: No relevant conflicts of interest to declare.

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