Sirtuins: not only animal proteins

Sirtuins are proteins belonging to the group of NADH-dependent deacetylase and mono-ADP-ribosyltransferase enzymes. Sirtuins have been discovered for the first time in yeasts, subsequent studies have shown their presence in bacteria, plants and animals. These enzymes are frequently called longevity enzymes due to the fact that they are part of genetic apparatus involved in aging control. In animals, sirtuins are key regulators of cell defense in response to stress caused by many metabolic processes; they are also involved in the regulation of cell division, metabolism, gene silencing and genetic material repair as well as apoptosis. Thus far, only several well-known research teams have been studying plant proteins resembling animal sirtuins. Considering the fact how essential functions sirtuins play in other organisms, it is extremely interesting to understand their role in plants, especially that the knowledge about them is still limited. It is believed that the function of sirtuins in Arabidopsis thaliana is associated with mitochondrial energy metabolism. Possibly they may also control the synthesis of auxins or proteins involved in their transport, or they may be responsible for regulating cellular response to auxin action. In rice, sirtuins are necessary for the protection against genomic instability and cell damage that guarantee their growth. They also take part in a defensive response against Pseudomonas syringae. They may also be involved in the ripening of fruits. Moreover, their functions are associated with photosynthetic activity and aging of leaves.     

Thyroid hormones and mitochondria

Because of their central role in the regulation of energy-transduction, mitochondria, the major site of oxidative processes within the cell, are considered a likely subcellular target for the action that thyroid hormones exert on energy metabolism. However, the mechanism underlying the regulation of basal metabolic rate (BMR) by thyroid hormones still remains unclear. It has been suggested that these hormones might uncouple substrate oxidation from ATP synthesis, but there are no clear-cut data to support this idea. Two iodothyronines have been identified as effectors of the actions of thyroid hormones on energy metabolism: 3',3,5-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2). Both have significant effects on BMR, but their mechanisms of action are not identical. T3 acts on the nucleus to influence the expression of genes involved in the regulation of cellular metabolism and mitochondria function; 3,5-T2, on the other hand, acts by directly influencing the mitochondrial energy-transduction apparatus. A molecular determinant of the effects of T3 could be uncoupling protein-3 (UCP-3), while the cytochrome-c oxidase complex is a possible target for 3,5-T2. In conclusion, it is likely that iodothyronines regulate energy metabolism by both short-term and long-term mechanisms, and that they act in more than one way in affecting mitochondrial functions.     

Cell energy metabolism: An update

In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes that take place during net biomass formation and maintenance processes. During growth, both ATP/ADP and NADH/NAD⁺ molecules play a key role. Cell energy metabolism hence refers to metabolic pathways involved in ATP synthesis linked to NADH turnover. Two main pathways are thus involved in cell energy metabolism: glycolysis/fermentation and oxidative phosphorylation. Glycolysis and mitochondrial oxidative phosphorylation are intertwined through thermodynamic and kinetic constraints that are reviewed herein. Further, our current knowledge of short-term and long term regulation of cell energy metabolism will be reviewed using examples such as the Crabtree and the Warburg effect.     

AMPK对线粒体功能的调节

5’单磷酸腺苷活化蛋白激酶（AMP—activated protein kinase,AMPK）是细胞的能量感受器,调节细胞能量代谢,在正常细胞和癌细胞中均发挥重要的生物功能,它的激活有助于纠正代谢紊乱,使细胞代谢趋向生理平衡。在细胞应急反应中,细胞感受到能量危机,ATP浓度下降,AMP浓度上升,细胞内AMP／ATP比例上升,AMPK被激活：而在病理状态下,如代谢综合征、肿瘤等,常伴随能量代谢紊乱和AMPK激活抑制,因此,AMPK被视为治疗代谢性疾病与肿瘤的潜在作用靶点。然而,AMPK对能量代谢的调节与线粒体的功能密不可分,线粒体作为细胞的能量工厂,在健康与疾病中也发挥着重要的作用。越来越多的研究表明,线粒体能影响AMPK的活性,同时AMPK也通过多方面对线粒体进行调节,线粒体相关疾病与AMPK的调节有着密切的关系。该文主要针对AMPK是如何对线粒体的合成、线粒体自噬、内源性凋亡及线粒体相关疾病等方面进行综述。     

Aspects of astrocyte energy metabolism,amino acid neurotransmitter homoeostasis and metabolic compartmentation

Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation.     

Lanthanum: inhibition of ACTH-stimulated cyclic AMP and corticosterone synthesis in isolated rat adrenocortical cells

Lanthanum (La+++) is a well-known Ca++ antagonist in a number of biological systems. It was used in the present study to examine the role of Ca++ in the regulation of adenyl cyclase of the adrenal cortex by ACTH. In micromolar concentrations, .La+++ inhibited both cyclic AMP and corticosterone response of isolated adrenal cortex cells to ACTH. However, a number of intracellular processes were not affected by La+++. These include the stimulation of steroidogenesis by dibutyryl cyclic AMP, conversion of several steroid precursors into corticosterone, and stimulation of the latter by glucose. Thus, inhibition of steroidogenesis by La+++ appears to be solely due to an inhibition of ACTH-stimulated cyclic AMP formation. Electron microscope examination showed that La+++ was localized on plasma membrane of the cells and did not appear to penetrate beyond this region. Since La+++ is believed to replace Ca++ at superficial binding sites on the cell membrane, it is proposed that Ca++ at these sites plays an important role in the regulation of adenyl cyclase by ACTH. Similarities in the role of Ca++ in "excitation-contraction" coupling and in the ACTH-adenyl cyclase system raise the possibility that a contractile protein may be involved in the regulation of adenyl cyclase by those hormones which are known to require Ca++ in the process.     

Methionine supplementation stimulates mitochondrial respiration

Mitochondria play essential metabolic functions in eukaryotes. Although their major role is the generation of energy in the form of ATP, they are also involved in maintenance of cellular redox state, conversion and biosynthesis of metabolites and signal transduction. Most mitochondrial functions are conserved in eukaryotic systems and mitochondrial dysfunctions trigger several human diseases.By using multi-omics approach, we investigate the effect of methionine supplementation on yeast cellular metabolism, considering its role in the regulation of key cellular processes. Methionine supplementation induces an up-regulation of proteins related to mitochondrial functions such as TCA cycle, electron transport chain and respiration, combined with an enhancement of mitochondrial pyruvate uptake and TCA cycle activity. This metabolic signature is more noticeable in cells lacking Snf1/AMPK, the conserved signalling regulator of energy homeostasis. Remarkably, snf1Δ cells strongly depend on mitochondrial respiration and suppression of pyruvate transport is detrimental for this mutant in methionine condition, indicating that respiration mostly relies on pyruvate flux into mitochondrial pathways.These data provide new insights into the regulation of mitochondrial metabolism and extends our understanding on the role of methionine in regulating energy signalling pathways.     

Endoplasmic reticulum stress-induced apoptosis accompanies enhanced expression of multiple inositol polyphosphate phosphatase 1 (Minpp1): a possible role for Minpp1 in cellular stress response

Inositol polyphosphates represent a group of differentially phosphorylated inositol metabolites, many of which are implicated to regulate diverse cellular processes such as calcium mobilization, vesicular trafficking, differentiation, apoptosis, etc. The metabolic network of these compounds is complex and tightly regulated by various kinases and phosphatases present predominantly in the cytosol. Multiple inositol polyphosphate phosphatase 1 (Minpp1) is the only known endoplasmic reticulum (ER) luminal enzyme that hydrolyzes various inositol polyphosphates in vitro as well as in vivo conditions. However, access of the Minpp1 to cytosolic substrates has not yet been demonstrated clearly and hence its physiological function. In this study, we examined a potential role for Minpp1 in ER stress-induced apoptosis. We generated a custom antibody and characterized its specificity to study the expression of Minpp1 protein in multiple mammalian cells under experimentally induced cellular stress conditions. Our results demonstrate a significant increase in the expression of Minpp1 in response to a variety of cellular stress conditions. The protein expression was corroborated with the expression of its mRNA and enzymatic activity. Further, in an attempt to link the role of Minpp1 to apoptotic stress, we studied the effect of Minpp1 expression on apoptosis following silencing of the Minpp1 gene by its specific siRNA. Our results suggest an attenuation of apoptotic parameters following knockdown of Minpp1. Thus, in addition to its known role in inositol polyphosphate metabolism, we have identified a novel role for Minpp1 as a stress-responsive protein. In summary, our results provide, for the first time, a probable link between ER stress-induced apoptosis and Minpp1 expression.     

Sphingolipid homeostasis in the web of metabolic routes

Sphingolipids play a key role in cells as structural components of membrane lipid bilayers and signaling molecules implicated in important physiological and pathological processes. Their metabolism is tightly regulated. Mechanisms controlling sphingolipid metabolism are far from being completely understood. However, they already reveal the integration of sphingolipids in the whole metabolic network as signaling devices that coordinate different metabolic pathways. A picture of sphingolipids integrated into metabolic networks might help to understand sphingolipid homeostasis. This review describes recent advances in the regulation of de novo sphingolipid synthesis with a focus on the bridges that exist with other metabolic pathways and the importance of this crosstalk in the control of sphingolipid homeostasis. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

The Mitochondrion: An Integration Point of Cellular Metabolism and Signalling

In addition to efficient synthesis of ATP by oxidative phosphorylation, acquisition of the mitochondrial endosymbiont brought a whole range of new metabolic capabilities to the ancestral eukaryotic cell lineage such that the mitochondrion retains an important role in numerous anabolic and catabolic processes. While respiration dominates metabolism of the mitochondrion, this organelle is also important in the catabolism of amino acids and the provision of carbon skeletons for biosynthesis of a wide range of compounds including amino acids, vitamins, lipids, and tetrapyrroles. However, mitochondrial metabolism is best understood in the context of cellular metabolism as a whole; this is particularly true in auxotrophic organisms such as plants. For this reason understanding of the integration of mitochondrial metabolism with associated metabolic pathways in distinct cellular locations is of great importance. The examples of photorespiration, proline, cysteine, branched chain amino acid, ascorbate and folate metabolism all indicate that mitochondrial steps in these pathways are critical to their function and regulation. Moreover, the central metabolic position of the mitochondrion and its key roles in bioenergetics and redox regulation, additionally mean that it is ideally placed to act as a sensor of the biochemical status of the cell. When taken together these observations suggest that the myriad nonrespiratory functions of the mitochondria are of vast importance in the coordination of plant cellular metabolism and function.     

拟南芥中myo-肌醇-多磷酸合成与代谢及其信号

在酵母、真菌、动物和植物等真核生物中, 以myo-肌醇为基石通过不同位点的磷酸化形成各种myo-肌醇-多磷酸及其衍生物。过去10年的研究发现这些肌醇多磷酸参与了膜脂定向转运、蛋白结构稳定、离子通道调控、RNA转运以及DNA修复和染色质重塑等细胞生物学的基本进程。近些年在模式植物拟南芥(Arabidopsis thaliana)的研究中, 许多调控植物生长发育和环境胁迫应答的重要基因被发现, 并证实这些基因参与myo-肌醇-多磷酸的合成与代谢。该文概述了拟南芥中myo-肌醇-多磷酸合成与代谢的基因调控机理, 综述了不同肌醇多磷酸作为信号分子的功能, 提出肌醇多磷酸如同一类信息代码传递着植物细胞有序进程的基本指令。     

靶向宿主代谢重编程的溶瘤病毒调控策略

溶瘤病毒是一类天然的或经过基因编辑后能特异性在肿瘤细胞中复制、发挥抗肿瘤效应的病毒。溶瘤病毒的抗肿瘤效应主要通过以下两个方面实现：a. 直接的溶瘤效应，例如诱导肿瘤细胞发生凋亡、促使细胞裂解等；b. 溶瘤病毒作为一种激活免疫的药物，通过诱导机体产生强烈的抗肿瘤免疫，达到清除肿瘤的目的。溶瘤病毒疗法作为免疫疗法的一个重要分支，因其具有肿瘤特异性，便于基因改造等优点，成为该领域的研究热点。截至目前，处在临床实验招募和完成阶段的溶瘤病毒疗法虽然已达100多例，但已批准上市的产品仅有4款。溶瘤疗法应用于肿瘤治疗领域还面临着诸多挑战。因此，系统性回顾溶瘤病毒的改造策略，深入了解溶瘤病毒的生物学过程显得尤为必要。病毒依赖于宿主完成复制、增殖过程，其生物学过程与宿主的代谢状态密切相关。肿瘤的标志性特征为代谢重编程，即肿瘤细胞重新构建代谢网络以满足指数生长和增殖的需求并防止氧化应激的过程。通常包括糖酵解的增强和谷氨酰胺分解，以及线粒体功能和氧化还原稳态的变化。通过靶向宿主代谢重编程增强溶瘤病毒的复制、溶瘤能力是当前极具前景的方向。本文综述溶瘤病毒的临床应用现状及与代谢相关的调控机制，为进一步开发新型溶瘤病毒以及联用方式提供新的思路。     

Inorganic Polyphosphate and Cancer

This review presents data on the relationship between inorganic polyphosphate metabolism and carcinogenesis including participation of polyphosphates in the regulation of activity of mTOR and other proteins involved in carcinogenesis, the role of h-prune protein (human polyphosphatase) in cell migration and metastasis formation, the prospects for using polyphosphates and inhibitors of polyphosphate metabolism enzymes as agents for controlling cell proliferation and migration.     

Histochemical studies in stomatal apparatus of Phaseolus mungo Linn, Lathyrus sativus Linn and Opuntia elatior Mill

With histochemical methods the distribution of some enzymes and metabolic substances in the epidermal peelings of Phaseolus mungo, Lathyrus sativus, and Opuntia elatior under light and dark conditions is examined. Dehydrogenases oxidases, transferases and hydrolases were studied. Fluctuations in the activity of hydrolases, especially, acid phosphatase, lipase, glucose-6-phosphatase, adenosine triphosphatase, dehydrogenases and transferases were observed during light and dark conditions. The role of such fluctuations in relation to stomatal regulation is discussed. Based on the present studies the following is suggested; stomatal opening and closing is related to structural and metabolic changes, and these changes are brought about by sugar gradients in the guard cells; light is enhancing the synthesis of sugars and some hormones, and besides this it stimulates membrane bound adenyl cyclase and release of cyclic AMP which affects the permeability; subsidiary cells actively participate in the stomatal physiology. Lysosomal hydrolytic enzymes like acid phosphatase are actively involved in catabolic phase of normal guard cells metabolism and regulate the osmotic pressure of the guard cells.     

Cell cycle regulators in cancer cell metabolism

Cancer proliferation and progression involves altered metabolic pathways as a result of continuous demand for energy and nutrients. In the last years, cell cycle regulators have been involved in the control of metabolic processes, such as glucose and insulin pathways and lipid synthesis, in addition to their canonical function controlling cell cycle progression. Here we describe recent data demonstrating the role of cell cycle regulators in the metabolic control especially in studies performed in cancer models. Moreover, we discuss the importance of these findings in the context of current cancer therapies to provide an overview of the relevance of targeting metabolism using inhibitors of the cell cycle regulation.