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.

scholarly journals Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

2021 ◽  
Vol 8 ◽  
Author(s):  
Felipe Muñoz-Córdova ◽  
Carolina Hernández-Fuentes ◽  
Camila Lopez-Crisosto ◽  
Mayarling F. Troncoso ◽  
Ximena Calle ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Clinical Manifestations ◽  
Myocardial Cell ◽  
Cardiomyocyte Hypertrophy ◽  
Autophagic Flux ◽  
Low Grade ◽  
Cellular Processes ◽  
Pharmacological Targets

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes developed mainly in poorly controlled patients. In DCM, several clinical manifestations as well as cellular and molecular mechanisms contribute to its phenotype. The production of reactive oxygen species (ROS), chronic low-grade inflammation, mitochondrial dysfunction, autophagic flux inhibition, altered metabolism, dysfunctional insulin signaling, cardiomyocyte hypertrophy, cardiac fibrosis, and increased myocardial cell death are described as the cardinal features involved in the genesis and development of DCM. However, many of these features can be associated with broader cellular processes such as inflammatory signaling, mitochondrial alterations, and autophagic flux inhibition. In this review, these mechanisms are critically discussed, highlighting the latest evidence and their contribution to the pathogenesis of DCM and their potential as pharmacological targets.

Novel treatments and future directions

2018 ◽  
Author(s):  
Seiya Miyamoto ◽  
Nobumi Miyake
Keyword(s):  
Negative Symptoms ◽  
Molecular Mechanisms ◽  
Antipsychotic Treatment ◽  
Treatment Resistant ◽  
Pharmacological Interventions ◽  
Future Directions ◽  
Novel Treatments ◽  
Medical Needs ◽  
Pharmacological Targets ◽  
New Generation

The advent of new-generation antipsychotic drugs has broadened the options for the pharmacological treatment of schizophrenia. However, there are still medical needs not met by current antipsychotic treatment, particularly for patients with negative symptoms and cognitive impairments, and for treatment-resistant schizophrenia. A growing body of research has identified new molecular mechanisms and novel pharmacological targets for treating schizophrenia beyond just dopamine D2 antagonism. This chapter provides a review of compounds in development and emerging non-pharmacological interventions for schizophrenia, and also considers approaches towards personalized and precision medicine for the disorder.

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.

Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2–AMPK–PGC1α signaling pathway

2019 ◽  
Vol 97 (4) ◽  
pp. 397-405 ◽  
Author(s):  
Bing Liu ◽  
Jiangbo Jin ◽  
Ziyu Zhang ◽  
Li Zuo ◽  
Meixiu Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Antitumor Activity ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathway ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Tricarboxylic Acid Cycle ◽  
Dependent Manner ◽  
Promising Therapeutic Approach

Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon, exhibits broad-spectrum antitumor activity via different molecular mechanisms. In this study, we investigated the effect of shikonin on mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanisms underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1α pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2–AMPK–PGC1α signaling pathway and provide a promising therapeutic approach for the treatment of HCC.

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.

scholarly journals Weaning differentially affects mitochondrial function, oxidative stress, inflammation and apoptosis in normal and low birth weight piglets

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247188
Author(s):  
Aliny K. Novais ◽  
Karine Deschêne ◽  
Yan Martel-Kennes ◽  
Caroline Roy ◽  
Jean-Paul Laforest ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Antioxidant Defenses ◽  
Inflammatory Status ◽  
And Oxidative Stress

Weaning is associated with increased occurrence of infections and diseases in piglets. Recent findings indicate that weaning induces mitochondrial dysfunction and oxidative stress conditions that more severely impact smaller piglets. The objective of this study was to characterize the molecular mechanisms underlying these physiological consequences and the relation with systemic inflammatory status in both normal and low birth weight (NBW and LBW) piglets throughout the peri-weaning period. To conduct the study, 30 sows were inseminated, and specific piglets from their litters were assigned to one of two experimental groups: NBW (n = 60, 1.73 ± 0.01 kg,) and LBW piglets weighing less than 1.2 kg (n = 60, 1.01 ± 0.01 kg). Then, 10 piglets from each group were selected at 14, 21 (weaning), 23, 25, 29 and 35 days of age to collect organ and plasma samples. Specific porcine RT2 Profiler™ PCR Arrays related to mitochondrial function, oxidative stress, inflammation and apoptosis processes were first used to target genes that are modulated after weaning in NBW piglets (d 23 and d 35 vs. d 14). Expression of selected genes was evaluated by quantitative PCR. These analyses revealed that expression of inflammatory genes CXCL10 and CCL19 increased after weaning in intestinal mucosa, while expression of genes encoding subunits of the mitochondrial respiratory chain was downregulated in liver and kidney of both groups. Interestingly, major modulators of mitophagy (BNIP3), cell survival (BCL2A1) and antioxidant defense system (TXNRD2, GPx3, HMOX1) were found to be highly expressed in NBW piglets. The systemic levels of TNF-α and IL1-β significantly increased following weaning and were higher in NBW piglets. These results provide novel information about the molecular origin of mitochondrial dysfunction and oxidative stress observed in weaned piglets and suggest that clearance of dysfunctional mitochondria, antioxidant defenses and inflammatory response are compromised in LBW piglets.

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.

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