Thematic Review Series: Recent Advances in the Treatment of Lysosomal Storage Diseases: Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Lysosomes play a vital role in the maintenance of cellular homeostasis through the recycling of cell constituents, a key metabolic function which is highly dependent on the correct function of the lysosomal hydrolases and membrane proteins, as well as correct membrane lipid stoichiometry and composition. The critical role of lysosomal functionality is evident from the severity of the diseases in which the primary lesion is a genetically defined loss-of-function of lysosomal hydrolases or membrane proteins. This group of diseases, known as lysosomal storage diseases (LSDs), number more than 50 and are associated with severe neurodegeneration, systemic disease, and early death, with only a handful of the diseases having a therapeutic option. Another key homeostatic system is the metabolic stress response or heat shock response (HSR), which is induced in response to a number of physiological and pathological stresses, such as protein misfolding and aggregation, endoplasmic reticulum stress, oxidative stress, nutrient deprivation, elevated temperature, viral infections, and various acute traumas. Importantly, the HSR and its cardinal members of the heat shock protein 70 family has been shown to protect against a number of degenerative diseases, including severe diseases of the nervous system. The cytoprotective actions of the HSR also include processes involving the lysosomal system, such as cell death, autophagy, and protection against lysosomal membrane permeabilization, and have shown promise in a number of LSDs. This review seeks to describe the emerging understanding of the interplay between these two essential metabolic systems, the lysosomes and the HSR, with a particular focus on their potential as a therapeutic target for LSDs.     

VLDL and HDL attenuate endoplasmic reticulum and metabolic stress in HL-1 cardiomyocytes

Lipoproteins have a vital role in the development of metabolic and cardiovascular diseases ranging from protective to deleterious effects on target tissues. VLDL has been shown to induce lipotoxic lipid accumulation and exert a variety of negative effects on cardiomyocytes. Lipotoxicity and endoplasmic reticulum (ER) stress are proposed to be the mediators of damaging effects of metabolic diseases on cardiovascular system. We treated cardiomyocytes with lipoproteins to evaluate the adaptability of these cells to metabolic stress induced by starvation and excess of lipoproteins, and to evaluate the effect of lipoproteins and lipid accumulation on ER stress. VLDL reversed metabolic stress induced by starvation, while HDL did not. VLDL induced dose-dependent lipid accumulation in cardiomyocytes, which however did not result in reduced cell viability or induction of ER stress. Moreover, VLDL or HDL pre-treatment reduced ER stress in cardiomyocytes induced by tunicamycin and palmitic acid as measured by the expression of ER stress markers, even in conditions of increased lipid accumulation. VLDL and HDL induced activation of pro-survival ERK1/2 in cardiomyocytes; however, this activation was not involved in the protection against ER stress. Additionally, we observed that LDLR and VLDLR are regulated differently by lipoproteins and cellular stress, as lipoproteins induced VLDLR protein independently of the level of lipid accumulation. We conclude that VLDL is not a priori detrimental for cardiomyocytes and can even have beneficial effects, enabling cell survival under starvation and attenuating ER stress.     

Oxidative stress and diabetes: What can we learn about insulin resistance from antioxidant mutant mouse models?

The development of metabolic dysfunctions like diabetes and insulin resistance in mammals is regulated by a myriad of factors. Oxidative stress seems to play a central role in this process as recent evidence shows a general increase in oxidative damage and a decrease in oxidative defense associated with several metabolic diseases. These changes in oxidative stress can be directly correlated with increased fat accumulation, obesity, and consumption of high-calorie/high-fat diets. Modulation of oxidant protection through either genetic mutation or treatment with antioxidants can significantly alter oxidative stress resistance and accumulation of oxidative damage in laboratory rodents. Antioxidant mutant mice have previously been utilized to examine the role of oxidative stress in other disease models, but have been relatively unexplored as models to study the regulation of glucose metabolism. In this review, we will discuss the evidence for oxidative stress as a primary mechanism linking obesity and metabolic disorders and whether alteration of antioxidant status in laboratory rodents can significantly alter the development of insulin resistance or diabetes.     

Role and function of macrophages in the metabolic syndrome

Macrophages are key innate immune effector cells best known for their role as professional phagocytes, which also include neutrophils and dendritic cells. Recent evidence indicates that macrophages are also key players in metabolic homoeostasis. Macrophages can be found in many tissues, where they respond to metabolic cues and produce pro- and/or anti-inflammatory mediators to modulate metabolite programmes. Certain metabolites, such as fatty acids, ceramides and cholesterol crystals, elicit inflammatory responses through pathogen-sensing signalling pathways, implicating a maladaptation of macrophages and the innate immune system to elevated metabolic stress associated with overnutrition in modern societies. The outcome of this maladaptation is a feedforward inflammatory response leading to a state of unresolved inflammation and a collection of metabolic pathologies, including insulin resistance, fatty liver, atherosclerosis and dyslipidaemia. The present review summarizes what is known about the contributions of macrophages to metabolic diseases and the signalling pathways that are involved in metabolic stress-induced macrophage activation. Understanding the role of macrophages in these processes will help us to develop therapies against detrimental effects of the metabolic syndrome.     

GDF15 as a central mediator for integrated stress response and a promising therapeutic molecule for metabolic disorders and NASH

BackgroundMitochondria is a key organelle for energy production and cellular adaptive response to intracellular and extracellular stresses. Mitochondrial stress can be evoked by various stimuli such as metabolic stressors or pathogen infection, which may lead to expression of ‘mitokines’ such as growth differentiation factor 15 (GDF15).Scope of reviewThis review summarizes the mechanism of GDF15 expression in response to organelle stress such as mitochondrial stress, and covers pathophysiological conditions or diseases that are associated with elevated GDF15 level. This review also illustrates the in vivo role of GDF15 expression in those stress conditions or diseases, and a potential of GDF15 as a therapeutic agent against metabolic disorders such as NASH.Major conclusionsMitochondrial unfolded protein response (UPRmt) is a critical process to recover from mitochondrial stress. UPRmt can induce expression of secretory proteins that can exert systemic effects (mitokines) as well as mitochondrial chaperons. GDF15 can have either protective or detrimental systemic effects in response to mitochondrial stresses, suggesting its role as a mitokine. Mounting evidence shows that GDF15 is also induced by stresses of organelles other than mitochondria such as endoplasmic reticulum (ER). GDF15 level is increased in serum or tissue of mice and human subjects with metabolic diseases such as obesity or NASH. GDF15 can modulate metabolic features of those diseases.General significanceGDF15 play a role as an integrated stress response (ISR) beyond mitochondrial stress response. GDF15 is involved in the pathogenesis of metabolic diseases such as NASH, and also could be a candidate for therapeutic agent against those diseases.     

脂肪组织氧化应激与运动干预

脂肪组织在调控代谢稳态和运动适应中扮演着重要的角色。肥胖引起的脂肪组织氧化应激是2型糖尿病与代谢综合征等的重要病理特征,是促进脂肪组织炎症和胰岛素抵抗的重要机制。氧化应激可以引起脂肪细胞趋化因子表达,募集炎症细胞浸润脂肪组织,炎症细胞分泌大量的炎症因子,并促进了局部和系统的胰岛素抵抗与慢性炎症。运动对肥胖相关的慢性代谢病的有效干预与运动的抗氧化效应相关。本文总结了氧化应激在脂肪组织炎症和胰岛素抵抗中的作用,以及运动对脂肪组织氧化应激的调控。     

Why sick cells produce tumors: the protective role of autophagy

Cells exploit autophagy for survival to metabolic stress in vitro as well as in tumors where it localizes to regions of metabolic stress suggesting its role as a survival pathway. Consistent with this survival function, deficiency in autophagy impairs cell survival, but also promotes tumor growth, creating a paradox that the loss of a survival pathway leads to tumorigenesis. There is evidence that autophagy is a homeostatic process functioning to limit the accumulation of poly-ubiquitinated proteins and mutant protein aggregates associated with neuronal degeneration. Interestingly, we found that deficiency in autophagy caused by monoallelic loss of beclin1 or deletion of atg5 leads to accelerated DNA damage and chromosomal instability demonstrating a mutator phenotype. These cells also exhibit enhanced chromosomal gains or losses suggesting that autophagy functions as a tumor suppressor by limiting chromosomal instability. Thus the impairment of survival to metabolic stress due to deficiency in autophagy may be compensated by an enhanced mutation rate thereby promoting tumorigenesis. The protective role of autophagy may be exploited in developing novel autophagy modulators as rational chemotherapeutic as well as chemopreventive agents.     

Targeting of stress response pathways in the prevention and treatment of cancer

The hallmarks of tumor tissue are not only genetic aberrations but also the presence of metabolic and oxidative stress as a result of hypoxia and lactic acidosis. The stress activates several prosurvival pathways including metabolic remodeling, autophagy, antioxidant response, mitohormesis, and glutaminolysis, whose upregulation in tumors is associated with a poor survival of patients, while their activation in healthy tissue with statins, metformin, physical activity, and natural compounds prevents carcinogenesis. This review emphasizes the dual role of stress response pathways in cancer and suggests the integrative understanding as a basis for the development of rational therapy targeting the stress response.     

哺乳动物低氧应激代谢成因的研究进展

氧气是哺乳动物机体代谢稳态维持的物质基础,若代谢过程中氧气供给不足,可造成低氧应激。目前,环境低氧、代谢性低氧和携氧细胞功能障碍是造成动物低氧应激的重要成因。目前,低氧对动物机体代谢和组织功能的影响研究主要集中于肺脏、肝脏、消化道、肌肉和乳腺等部位。若处于低氧状态的哺乳动物形成了适应低氧的代谢模式,则可维持其代谢稳态;相反,若动物无法维持低氧状态下的代谢稳态,则会导致机体氧化应激甚至病变。目前,低氧应激在家畜方面的研究主要集中于高原动物代谢适应机制;然而,泌乳期动物机体代谢速率、氧气消耗和自由基水平均较高,但氧在泌乳动物代谢应激形成中的作用及其对泌乳性能的影响,仍有待探索。综述了哺乳动物产生低氧应激的代谢成因与作用结果,旨在探讨哺乳动物低氧应激生物学基础,为进一步从低氧应激调控角度为泌乳动物的健康状况维持提供理论依据。     

Salt tolerance of barley induced by the root endophyte Piriformospora indica is associated with a strong increase in antioxidants

The root endophytic basidiomycete Piriformospora indica has been shown to increase resistance against biotic stress and tolerance to abiotic stress in many plants. Biochemical mechanisms underlying P. indica-mediated salt tolerance were studied in barley (Hordeum vulgare) with special focus on antioxidants. Physiological markers for salt stress, such as metabolic activity, fatty acid composition, lipid peroxidation, ascorbate concentration and activities of catalase, ascorbate peroxidase, dehydroascorbate reductase, monodehydroascorbate reductase and glutathione reductase enzymes were assessed. Root colonization by P. indica increased plant growth and attenuated the NaCl-induced lipid peroxidation, metabolic heat efflux and fatty acid desaturation in leaves of the salt-sensitive barley cultivar Ingrid. The endophyte significantly elevated the amount of ascorbic acid and increased the activities of antioxidant enzymes in barley roots under salt stress conditions. Likewise, a sustained up-regulation of the antioxidative system was demonstrated in NaCl-treated roots of the salt-tolerant barley cultivar California Mariout, irrespective of plant colonization by P. indica. These findings suggest that antioxidants might play a role in both inherited and endophyte-mediated plant tolerance to salinity.     

Free Radicals as Mediators of Neuronal Injury

1. Free radicals may play an important role in several pathological conditions of the central nervous system (CNS) where they directly injure tissue and where their formation may also be a consequence of tissue injury.2. Free radicals produce tissue damage through multiple mechanisms, including excitotoxicity, metabolic dysfunction, and disturbance of intracellular homeostasis of calcium.3. Oxidative stress can significantly worsen acute insults, such as ischemia, as well as chronic neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease.4. For instance, recent findings suggest a causal role for chronic oxidative stress in familial ALS, as this disease is linked to missence mutations of the copper/zinc superoxide dismutase (SOD).5. Thus, therapeutic approaches which limit oxidative stress may be potentially beneficial in several neurological diseases.     

Stress mechanisms and metabolic complications.

Stress can be defined as a state of threatened homeostasis or disharmony. An intricate repertoire of physiologic and behavioral responses is mobilized under stressful situations forming the adaptive stress response that aims to reestablish the challenged body equilibrium. The hypothalamic-pituitary-adrenal axis and the central and peripheral components of the autonomic nervous system constitute the two main pillars that subserve the vital functions of the stress system. Chronic stress represents a prolonged threat to homeostasis that can progressively lead to a deleterious overload with various complications caused by both the persistent stressor and the detrimental prolongation of the adaptive response. Recent data indicate that chronic stress is associated to derangement of metabolic homeostasis that contributes to the clinical presentation of visceral obesity, type 2 diabetes, atherosclerosis and metabolic syndrome. Notably, indices of stress in the modern western societies correlate with the increasing incidence of both obesity and the metabolic syndrome which have reached epidemic proportions over the past decades. The pathogenetic mechanisms that accommodate these correlations implicate primarily the chronic hyperactivation of the HPA axis under prolonged stress, which favors accumulation of visceral fat, and VICE VERSA; obesity constitutes a chronic stressful state that may cause HPA axis dysfunction. In addition, obesity is being now recognized as a systemic low grade inflammatory state that contributes to the derangement of the metabolic equilibrium, implicating the adipocyte secretion of adipokines to the pathogenesis of several components of the metabolic syndrome. Understanding the mechanisms that mediate the documented reciprocal relationships between stress and metabolic homeostasis will hopefully provide novel insights to the pathophysiology of obesity, type 2 diabetes, and their cardiometabolic complications, and will help the quest for more specific and effective therapeutic interventions.     

The role of peroxisome proliferator activated receptors in metabolic balance disturbances under stress

Some aspects of peroxisome proliferator activated receptors (PPAR) involvement in regulation of stress-dependent biological processes leading to insulin resistance, lipid imbalance, hypertension and inflammation are reviewed. Analysis of literature data clearly shows the main role of PPAR in stress signal transduction following to metabolic disbalance development under prolonged stress conditions. The interplay of three PPAR isoforms functional activity with metabolic process disturbances during stress is under special emphasis. Taking into account experimental data described in literature we suggest that PPAR activation under acute stress is an adaptive response while stable PPAR hyperexpression under prolonged stress can cause insulin resistance, hypertension, and visceral obesity. The strategy of PPAR using as pharmacological targets in metabolic syndrome correction is under consideration.     

植物苯丙烷代谢及其对重金属胁迫的响应研究进展

苯丙烷代谢途径是植物中最重要的次生代谢途径之一,在植物抵抗重金属胁迫中直接或间接发挥了抗氧化作用,并能够提高植物对重金属离子的吸收与胁迫耐性。本文就苯丙烷代谢途径核心反应与关键酶系进行了总结,同时分析了木质素、类黄酮及原花青素等关键代谢产物的生物合成过程及相关机制,并以此为基础探讨了苯丙烷代谢途径关键产物响应重金属胁迫的相关机制。此外,结合当前研究现状,就苯丙烷代谢参与植物防御重金属胁迫的相关研究提出展望,以期为重金属污染环境的植物修复提供理论依据。     

Role of salicylic acid on physiological and biochemical mechanism of salinity stress tolerance in plants

Salinity stress is one of the major abiotic stresses affecting plant growth and productivity globally. In order to improve the yields of plants growing under salt stress bear remarkable importance to supply sustainable agriculture. Acclimation of plants to salinized condition depends upon activation of cascade of molecular network involved in stress sensing/perception, signal transduction, and the expression of specific stress-related genes and metabolites. Isolation of salt overly sensitive (SOS) genes by sos mutants shed us light on the relationship between ion homeostasis and salinity tolerance. Regulation of antioxidative system to maintain a balance between the overproduction of reactive oxygen species and their scavenging to keep them at signaling level for reinstating metabolic activity has been elucidated. However, osmotic adaptation and metabolic homeostasis under abiotic stress environment is required. Recently, role of phytohormones like Abscisic acid, Jasmonic acid, and Salicylic acid in the regulation of metabolic network under osmotic stress condition has emerged through crosstalk between chemical signaling pathways. Thus, abiotic stress signaling and metabolic balance is an important area with respect to increase crop yield under suboptimal conditions. This review focuses on recent developments on improvement in salinity tolerance aiming to contribute sustainable plant yield under saline conditions in the face of climate change.     

Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis

Although the biochemical steps linking insulin resistance with the metabolic syndrome have not been completely clarified, mounting experimental and clinical evidence indicate oxidative stress as an attractive candidate for a central pathogenic role since it potentially explains the appearance of all risk factors and supports the clinical manifestations. In fact, metabolic syndrome patients exhibit activation of biochemical pathways leading to increased delivery of reactive oxygen species, decreased antioxidant protection and increased lipid peroxidation. The described associations between increased abdominal fat storage, liver steatosis and systemic oxidative stress, the diminished concentration of nitric oxide derivatives and antioxidant vitamins and the endothelial oxidative damages observed in subjects with the metabolic syndrome definitively support oxidative stress as the common second-level event in a unifying pathogenic view. Moreover, it has been observed that oxidative stress regulates the expression of genes governing lipid and glucose metabolism through activation or inhibition of intracellular sensors. Diet constituents can modulate redox reactions and the oxidative stress extent, thus also acting on nuclear gene expression. As a consequence of the food-gene interaction, metabolic syndrome patients may express different disease features and extents according to the different pathways activated by oxidative stress-modulated effectors. This view could also explain family differences and interethnic variations in determining risk factor appearance. This review mechanistically focused on oxidative stress events leading to individual disease factor appearance in metabolic syndrome patients and their setting for a more helpful clinical approach.     

Cell‐to‐cell heterogeneity emerges as consequence of metabolic cooperation in a synthetic yeast community

Cells that grow together respond heterogeneously to stress even when they are genetically similar. Metabolism, a key determinant of cellular stress tolerance, may be one source of this phenotypic heterogeneity, however, this relationship is largely unclear. We used self‐establishing metabolically cooperating (SeMeCo) yeast communities, in which metabolic cooperation can be followed on the basis of genotype, as a model to dissect the role of metabolic cooperation in single‐cell heterogeneity. Cells within SeMeCo communities showed to be highly heterogeneous in their stress tolerance, while the survival of each cell under heat or oxidative stress, was strongly determined by its metabolic specialization. This heterogeneity emerged for all metabolite exchange interactions studied (histidine, leucine, uracil, and methionine) as well as oxidant (H₂O₂, diamide) and heat stress treatments. In contrast, the SeMeCo community collectively showed to be similarly tolerant to stress as wild‐type populations. Moreover, stress heterogeneity did not establish as sole consequence of metabolic genotype (auxotrophic background) of the single cell, but was observed only for cells that cooperated according to their metabolic capacity. We therefore conclude that phenotypic heterogeneity and cell to cell differences in stress tolerance are emergent properties when cells cooperate in metabolism.