scholarly journals Decreasing pdzd8-mediated mitochondrial-ER contacts in neurons improves fitness by increasing mitophagy

2020 ◽  
Author(s):  
Victoria L. Hewitt ◽  
Leonor Miller-Fleming ◽  
Simonetta Andreazza ◽  
Francesca Mattedi ◽  
Julien Prudent ◽  
...  
Keyword(s):  
Quality Control ◽  
Healthy Aging ◽  
Synapse Formation ◽  
Critical Role ◽  
Functional Characterization ◽  
Protective Effects ◽  
Mitochondrial Quality Control ◽  
Age Related ◽  
The Many

AbstractThe complex cellular architecture of neurons combined with their longevity makes maintaining a healthy mitochondrial network particularly important and challenging. One of the many roles of mitochondrial-ER contact sites (MERCs) is to mediate mitochondrial quality control through regulating mitochondrial turn over. Pdzd8 is a newly discovered MERC protein, the organismal functions of which have not yet been explored. Here we identify and provide the first functional characterization of the Drosophila melanogaster ortholog of Pdzd8. We find that reducing pdzd8-mediated MERCs in neurons slows age-associated decline in locomotor activity and increases lifespan in Drosophila. The protective effects of pdzd8 knockdown in neurons correlate with an increase in mitophagy, suggesting that increased mitochondrial turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER-mitochondria tether disrupts mitochondrial transport and synapse formation, accelerates age-related decline in locomotion and reduces lifespan. We also show that depletion of pdzd8 rescues the locomotor defects characterizing an Alzheimer’s disease (AD) fly model over-expressing Amyloidβ1–42 (Aβ42) and prolongs the survival of flies fed with mitochondrial toxins. Together, our results provide the first in vivo evidence that MERCs mediated by the tethering protein pdzd8 play a critical role in the regulation of mitochondrial quality control and neuronal homeostasis.

scholarly journals Autophagy in health and disease. 5. Mitophagy as a way of life

2010 ◽  
Vol 299 (2) ◽  
pp. C203-C210 ◽  
Author(s):  
Roberta A. Gottlieb ◽  
Raquel S. Carreira
Keyword(s):  
Quality Control ◽  
Fluorescent Protein ◽  
Mitochondrial Quality Control ◽  
Free Radical Theory ◽  
Radical Theory ◽  
Energy Needs ◽  
Tight Connection ◽  
The Many ◽  
Green Fluorescent

Our understanding of autophagy has expanded greatly in recent years, largely due to the identification of the many genes involved in the process and to the development of better methods to monitor the process, such as green fluorescent protein-LC3 to visualize autophagosomes in vivo. A number of groups have demonstrated a tight connection between autophagy and mitochondrial turnover. Mitochondrial quality control is the process whereby mitochondria undergo successive rounds of fusion and fission with a dynamic exchange of components to segregate functional and damaged elements. Removal of the mitochondrion that contains damaged components is accomplished via autophagy (mitophagy). Mitophagy also serves to eliminate the subset of mitochondria producing the most reactive oxygen species, and episodic removal of mitochondria will reduce the oxidative burden, thus linking the mitochondrial free radical theory of aging with longevity achieved through caloric restriction. Mitophagy must be balanced by biogenesis to meet tissue energy needs, but the system is tunable and highly dynamic. This process is of greatest importance in long-lived cells such as cardiomyocytes, neurons, and memory T cells. Autophagy is known to decrease with age, and the failure to maintain mitochondrial quality control through mitophagy may explain why the heart, brain, and components of the immune system are most vulnerable to dysfunction as organisms age.

scholarly journals RESEARCH OF NEW PHYTOADAPTOGENS AND POSSIBILITIES OF HERBAL FORMULAS APPLICATION

2020 ◽  
Vol 19 (4) ◽  
pp. 35-44
Author(s):  
O. A. Bocharova ◽  
R. V. Karpova ◽  
E. V. Bocharov ◽  
A. A. A.Vershinskaya ◽  
M. A. Baryshnikova ◽  
...  
Keyword(s):  
Pharmacological Action ◽  
Biologically Active ◽  
Herbal Formula ◽  
Protective Effects ◽  
Age Related ◽  
Rational Combination ◽  
Oplopanax Elatus ◽  
The Many

Classic phytoadaptogens (Panax ginseng, Rhodiola rosea, Aralia mandshurica, Oplopanax elatus, Eleutherococcus senticosus, Leuzea carthamoides, Schisandra chinensis) have a complex protective effects, increasing the antitumor control of organisms. However, resistance to some adaptogens can develop. Therefore, the elaboration of multicomponent phytoadaptogen complexes based on the principle of a rational combination of complementary biologically active substances are relevant and scientifically significant. The use of several adaptogens in the herbal formula considers the absence of the organisms resistance. The review presents Russian and foreign studies devoted to the search for potential phytoadaptogens, as well as the development of complexes based on them. The possibility of regulating the protective systems of organism by components of phytoextracts with different points of pharmacological action has been shown. The advantages of multicomponent phytomixtures in comparison with individual adaptogens are substantiated. The many-sided experimental in vitro and in vivo investigations of Russian herbal formula are colligated. Its clinical application has been demonstrated in relation to a benign tumour, precancerous disease, advanced cancer process, and neurodegenerative pathology. The prospects of using the herbal formula preparations as a part of integrative medicine including oncological and age-related pathologies are shown.

scholarly journals Dietary Antioxidants and the Mitochondrial Quality Control: Their Potential Roles in Parkinson’s Disease Treatment

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1056 ◽  
Author(s):  
Davin Lee ◽  
Min Gu Jo ◽  
Seung Yeon Kim ◽  
Chang Geon Chung ◽  
Sung Bae Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Life Expectancy ◽  
Mitochondrial Dysfunction ◽  
Healthy Aging ◽  
Human Life ◽  
Dietary Antioxidants ◽  
Mitochondrial Quality Control ◽  
Age Related

Advances in medicine and dietary standards over recent decades have remarkably increased human life expectancy. Unfortunately, the chance of developing age-related diseases, including neurodegenerative diseases (NDDs), increases with increased life expectancy. High metabolic demands of neurons are met by mitochondria, damage of which is thought to contribute to the development of many NDDs including Parkinson’s disease (PD). Mitochondrial damage is closely associated with the abnormal production of reactive oxygen species (ROS), which are widely known to be toxic in various cellular environments, including NDD contexts. Thus, ways to prevent or slow mitochondrial dysfunction are needed for the treatment of these NDDs. In this review, we first detail how ROS are associated with mitochondrial dysfunction and review the cellular mechanisms, such as the mitochondrial quality control (MQC) system, by which neurons defend against both abnormal production of ROS and the subsequent accumulation of damaged mitochondria. We next highlight previous studies that link mitochondrial dysfunction with PD and how dietary antioxidants might provide reinforcement of the MQC system. Finally, we discuss how aging plays a role in mitochondrial dysfunction and PD before considering how healthy aging through proper diet and exercise may be salutary.

scholarly journals Humanin is an endogenous activator of chaperone-mediated autophagy

2017 ◽  
Vol 217 (2) ◽  
pp. 635-647 ◽  
Author(s):  
Zhenwei Gong ◽  
Inmaculada Tasset ◽  
Antonio Diaz ◽  
Jaime Anguiano ◽  
Emir Tas ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Heat Shock Protein 90 ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Selective Degradation ◽  
Cytosolic Side ◽  
Chaperone Mediated Autophagy

Chaperone-mediated autophagy (CMA) serves as quality control during stress conditions through selective degradation of cytosolic proteins in lysosomes. Humanin (HN) is a mitochondria-associated peptide that offers cytoprotective, cardioprotective, and neuroprotective effects in vivo and in vitro. In this study, we demonstrate that HN directly activates CMA by increasing substrate binding and translocation into lysosomes. The potent HN analogue HNG protects from stressor-induced cell death in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. The protective effects are lost in CMA-deficient cells, suggesting that they are mediated through the activation of CMA. We identified that a fraction of endogenous HN is present at the cytosolic side of the lysosomal membrane, where it interacts with heat shock protein 90 (HSP90) and stabilizes binding of this chaperone to CMA substrates as they bind to the membrane. Inhibition of HSP90 blocks the effect of HNG on substrate translocation and abolishes the cytoprotective effects. Our study provides a novel mechanism by which HN exerts its cardioprotective and neuroprotective effects.

scholarly journals Receptor-mediated mitophagy regulates EPO production and protects against renal anemia

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Guangfeng Geng ◽  
Jinhua Liu ◽  
Changlu Xu ◽  
Yandong yan Pei ◽  
Linbo Chen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Quality Control ◽  
Therapeutic Strategy ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Renal Anemia ◽  
Inflammatory Factors ◽  
Oxygen Species ◽  
Mitochondrial Quality Control ◽  
Hematopoietic Disorders

Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.

Dynamic regulation of the voltage-gated Kv2.1 potassium channel by multisite phosphorylation

2007 ◽  
Vol 35 (5) ◽  
pp. 1064-1068 ◽  
Author(s):  
D.P. Mohapatra ◽  
K.-S. Park ◽  
J.S. Trimmer
Keyword(s):  
Neuronal Excitability ◽  
Critical Role ◽  
Functional Characterization ◽  
K Channel ◽  
Delayed Rectifier ◽  
Dynamic Regulation ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Specific Regulation

Voltage-gated K+ channels are key regulators of neuronal excitability. The Kv2.1 voltage-gated K+ channel is the major delayed rectifier K+ channel expressed in most central neurons, where it exists as a highly phosphorylated protein. Kv2.1 plays a critical role in homoeostatic regulation of intrinsic neuronal excitability through its activity- and calcineurin-dependent dephosphorylation. Here, we review studies leading to the identification and functional characterization of in vivo Kv2.1 phosphorylation sites, a subset of which contribute to graded modulation of voltage-dependent gating. These findings show that distinct developmental-, cell- and state-specific regulation of phosphorylation at specific sites confers a diversity of functions on Kv2.1 that is critical to its role as a regulator of intrinsic neuronal excitability.

scholarly journals Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury

2018 ◽  
Vol 19 (9) ◽  
pp. 2509 ◽  
Author(s):  
Jing Zhang ◽  
Xin Guo ◽  
Taiji Hamada ◽  
Seiya Yokoyama ◽  
Yuka Nakamura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Critical Role ◽  
Therapeutic Modality ◽  
Protective Effects ◽  
Fibrotic Liver ◽  
Intrahepatic Bile Ducts ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

Vasoactive intestinal peptide prevents PKCε-induced intestinal epithelial barrier disruption during EPEC infection

2015 ◽  
Vol 308 (5) ◽  
pp. G389-G402 ◽  
Author(s):  
V. Morampudi ◽  
V. S. Conlin ◽  
U. Dalwadi ◽  
X. Wu ◽  
K. C. Marshall ◽  
...  
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Critical Role ◽  
Term Treatment ◽  
Epithelial Barrier ◽  
Protective Effects ◽  
Short Term Treatment ◽  
Barrier Integrity ◽  
Barrier Disruption ◽  
Long Term Treatment

We previously showed that vasoactive intestinal peptide (VIP) protects against bacterial pathogen-induced epithelial barrier disruption and colitis, although the mechanisms remain poorly defined. The aim of the current study was to identify cellular pathways of VIP-mediated protection with use of pharmacological inhibitors during enteropathogenic Escherichia coli (EPEC) infection of Caco-2 cell monolayers and during Citrobacter rodentium-induced colitis. EPEC-induced epithelial barrier disruption involved the PKC pathway but was independent of functional cAMP, Rho, and NF-κB pathways. VIP mediated its protective effects by inhibiting EPEC-induced PKC activity and increasing expression of the junctional protein claudin-4. Short-term treatment with TPA, which is known to activate PKC, was inhibited by VIP pretreatment, while PKC degradation via long-term treatment with TPA mimicked the protective actions of VIP. Immunostaining for specific PKC isotypes showed upregulated expression of PKCθ and PKCε during EPEC infection. Treatment with specific inhibitors revealed a critical role for PKCε in EPEC-induced barrier disruption. Furthermore, activation of PKCε and loss of barrier integrity correlated with claudin-4 degradation. In contrast, inhibition of PKCε by VIP pretreatment or the PKCε inhibitor maintained membrane-bound claudin-4 levels, along with barrier function. Finally, in vivo treatment with the PKCε inhibitor protected mice from C. rodentium-induced colitis. In conclusion, EPEC infection increases intracellular PKCε levels, leading to decreased claudin-4 levels and compromising epithelial barrier integrity. VIP inhibits PKCε activation, thereby attenuating EPEC-induced barrier disruption.

The Indispensable Value of Clinical Trials in the Modernization of Traditional Chinese Medicine: 12 Years' Experience at CUHK and Future Perspectives

2014 ◽  
Vol 42 (03) ◽  
pp. 587-604 ◽  
Author(s):  
Willmann Liang ◽  
David T. Yew ◽  
Kam Lun Hon ◽  
Chun Kwok Wong ◽  
Timothy C. Y. Kwok ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chinese Medicine ◽  
Herbal Medicines ◽  
Chinese Herbs ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Artery Disease ◽  
The Many

The last decade has seen a wealth of information reporting the beneficial effects of Chinese herbal medicines. While a lot more studies were done using in vitro and in vivo research platforms, much fewer investigations were conducted according to evidence-based requirements in clinical settings. The Institute of Chinese Medicine at the Chinese University of Hong Kong (CUHK) has had the opportunity to collaborate with clinicians over the years to initiate and conduct dozens of clinical trials investigating and verifying the therapeutic values of Chinese herbs in selected disease conditions. Of the many disorders, we chose to focus on those that are known for their difficulties achieving perfect results with conventional treatment methods. Examples include non-healing ulcers, allergic conditions, degenerative diseases and cancer. Protective effects of the herbs in such chronic diseases as coronary artery disease and osteoporosis were also part of our focus. Even in healthy individuals and those recovering from chemotherapy, Chinese herbs could help with the immune system and were studied in our clinical trials as well. This paper aims to highlight the important findings from these clinical studies while at the same time, stressing the indispensable value of clinical trials in modernizing the use of Chinese herbs in present-day medicine.

scholarly journals Functional Characterization of Brain Tumor-Initiating Cells: Implications for Preclinical Models and Drug Development

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Cesar A Garcia ◽  
Adip Guruprasad Bhargav ◽  
Sujan K Mondal ◽  
Karim ReFaey ◽  
Natanael Zarco ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Critical Role ◽  
Functional Characterization ◽  
Tumor Initiating Cells ◽  
Retroviral Transduction ◽  
Significant Difference ◽  
Brain Tumor Initiating Cells ◽  
Functional Features

Abstract INTRODUCTION Glioblastoma (GBM) is the deadliest and most common primary brain cancer in adults. Brain tumor-initiating cells (BTICs) are a heterogeneous subset of stem-like, invasive cells that play a critical role in treatment failure and recurrence. METHODS Here, we propose a system to functionally characterize patient-derived BTICs to identify features that will guide assessment of therapeutics in a BTIC subpopulation-specific manner. We established and evaluated 5 BTIC populations based on (1) proliferation, (2) stemness, (3) migration, (4) tumorigenesis, (5) clinical characteristics, and (6) therapeutic sensitivity. RESULTS Overall, in Vitro growth trends reflected in Vivo growth rates. However, a significant difference was found between tumor growth in male versus female mice in 3 BTIC lines (QNS108 P = .0011; QNS120 P < .0001; QNS 140 P < .0001). Differences in survival were observed, where BTICs derived from male and female patients produced faster morbidity in mice of the opposite sex (male derived QNS108 male vs female P = .0039; female derived QNS203 male vs female P = .029). QNS203, which was isolated from a tumor in contact with the anterior subventricular zone, decreased survival at a faster rate compared to other cell lines (n = 10 per line, 5 males/5 females, P < .0001). Stem-like properties of BTICs were assessed via differentiation marker expression, sphere-forming capacity, and detection of canonical marker CD133. Higher CD133 expression correlated with faster in Vitro doubling time and greater tumor burden. Histology reflected similar patient tumor features such as migration across the corpus callosum and cystic formation. BTICs revealed varying responses to therapies (TMZ, Radiation, TRAIL, BMP4) and varied competence to retroviral transduction. CONCLUSION By studying the functional features of BTICs within our model of GBM heterogeneity, it was shown that several factors influenced tumorigenesis and survival. These included original tumor location, stemness, variation in therapeutic sensitivity, and a critical finding for the role of sex, an unexplored area for creating next-generation, sex-specific, and BTIC-specific therapeutics.

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