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。     

线粒体，活性氧和细胞凋亡

在能量代谢和自由基代谢中,线粒体均占据着十分重要的地位.通过呼吸链电子漏途径,线粒体产生大量超氧阴离子,并通过链式反应形成对机体有损伤作用的活性氧.通过呼吸链电子漏,氧化磷酸化解偶联,线粒体内膜产生通透性转变孔道（PTP）及Box-和/或PTP-介导的细胞色素c向胞质的转移等种种因素,线粒体参与一般抗氧化防御及细胞凋亡等重要生理过程的调控.在与线粒体相关的细胞凋亡中,活性氧的信号作用是十分明显的.     

脑能量代谢与线粒体功能关系的研究进展

线粒体是人体内的能量代谢工厂,而脑是人体内能量代谢最活跃的部位。神经元和胶质细胞是脑内主要的细胞。本文对线粒体在能量产生的作用进行综述,同时比较神经元和星形胶质细胞能量代谢的异同及密切联系,并对神经退行性变中能量代谢障碍与线粒体可塑性改变进行了回顾。以三种神经退行性疾病帕金森、阿尔兹海默和脊髓侧索硬化症为例说明线粒体在神经系统疾病和脑能量代谢之间的重要作用。从而进一步系统的认识,脑内的线粒体在生理和病理状态下对能量代谢的影响。深入了解其机制,为研究神经系统退行性疾病提供新的治疗策略。     

线粒体功能异常与肿瘤的生成

肿瘤的发生是一个多种信号网络相互参与调节的复杂过程,随着进程的继续,肿瘤细胞逐渐表现出无限增殖、抵抗凋亡、逃避免疫监督、侵袭与转移以及出现异常的代谢途径等标志性特征。线粒体作为一种独特的细胞器,其在细胞能量代谢、氧自由基生成和细胞凋亡等过程中的作用都与肿瘤细胞的发生密切相关。文中就近年来线粒体功能异常在肿瘤发生、形成中所发挥的作用进行综述。     

线粒体融合蛋白Mfn1/2的结构和功能

线粒体融合素基因（mitofusin gene,Mfn）在哺乳动物中编码两种蛋白质分子,Mfn1和Mfn2,它们在线粒体融合、分裂与细胞凋亡中起重要作用,调控着线粒体形态的动态变化。另外,Mfn1/2还参与线粒体的能量代谢并与相关疾病的发生有着密切关系。     

交替氧化酶和解偶联蛋白在植物线粒体中的作用及其相互关系

植物线粒体不仅含有细胞色素C呼吸途径相关蛋白,也包括交替氧化酶（抗氰交替途径）和解偶联蛋白（解偶联途径）,这些途径中的蛋白都直接影响植物线粒体能量代谢。本文介绍了交替氧化酶和解偶联蛋白在植物线粒体能量代谢中的作用及其相互关系的研究进展。     

人线粒体RNA加工及调控

线粒体是细胞内氧化磷酸化（oxidative phosphorylation,OXPHOS）和合成三磷酸腺苷（adenosine triphosphate,ATP）的细胞器，是细胞能量代谢的“动力工厂”。线粒体几乎存在于所有真核生物中，参与细胞凋亡、钙稳态以及先天免疫反应的调节等过程，对细胞行使正常的生理功能至关重要。线粒体是半自主细胞器，拥有自身的基因组DNA，编码37个基因，包括2个rRNA基因、13个m RNA基因和22个tRNA基因。线粒体的基因表达需要经过复杂的转录和转录后加工过程，包括多顺反子RNA的切割、RNA的修饰以及RNA的末端加工等过程。异常的线粒体RNA加工会导致线粒体RNA表达谱发生变化、线粒体翻译紊乱、线粒体功能失常等，从而造成多种线粒体相关疾病。本文综述了线粒体DNA的转录、RNA转录后加工以及影响RNA加工的因素方面的最新研究进展。     

Parkin介导的线粒体自噬及细胞器互作机制

线粒体是细胞生理代谢活动发生的重要场所. 线粒体生发降解平衡是维持能量代谢稳定的重要保障. Parkin作为E3泛素连接酶，通过PINK1/Parkin、LC3等多种信号参与调控线粒体自噬过程. 此外，Parkin还能够影响线粒体相关内质网膜、调控细胞器间钙流，在线粒体-内质网对话过程中调控溶酶体途径介导的线粒体自噬. 脂肪组织是研究线粒体调节机制的理想模型：寒冷刺激诱导富含线粒体的米色脂肪生成；移除刺激后，组织中线粒体消失恢复为白色脂肪，但线粒体稳定性的调控机理目前仍有很多未知. 本文综述Parkin介导线粒体自噬途径的最新研究进展，及其参与线粒体、内质网、溶酶体等不同细胞器间相互作用的调控机制.     

miRNA调控线粒体功能的研究进展

MiRNA为小分子非编码RNA,通过与靶基因的相互作用调节靶基因的表达,参与调控细胞的多个生物学过程。本文综述了miRNA与线粒体生物合成、线粒体动力学、线粒体能量代谢、线粒体钙稳态、线粒体自噬间的关系及其调节机制,阐述了microRNA调节线粒体功能的研究进展。     

细胞核基因组和线粒体基因组的相互作用

线粒体DNA是细胞内唯一的核外遗传物质,线粒体的主要功能是合成ATP,为细胞生命活动提供直接能量。线粒体基因组与核基因组在基因、蛋白以及细胞水平上相互作用,共同保证细胞能量代谢有关的活动,维持着线粒体的正常功能和细胞的正常状态。     

Mitoenergetic failure in Alzheimer disease

Brain cells are highly energy dependent for maintaining ion homeostasis during high metabolic activity. During active periods, full mitochondrial function is essential to generate ATP from electrons that originate with the oxidation of NADH. Decreasing brain metabolism is a significant cause of cognitive abnormalities of Alzheimer disease (AD), but it remains uncertain whether this is the cause of further pathology or whether synaptic loss results in a lower energy demand. Synapses are the first to show pathological symptoms in AD before the onset of clinical symptoms. Because synaptic function has high energy demands, interruption in mitochondrial energy supply could be the major factor in synaptic failure in AD. A newly discovered age-related decline in neuronal NADH and redox ratio may jeopardize this function. Mitochondrial dehydrogenases and several mutations affecting energy transfer are frequently altered in aging and AD. Thus, with the accumulation of genetic defects in mitochondria at the level of energy transfer, the issue of neuronal susceptibility to damage as a function of age and age-related disease becomes important. In an aging rat neuron model, mitochondria are both chronically depolarized and produce more reactive oxygen species with age. These concepts suggest that multiple treatment targets may be needed to reverse this multifactorial disease. This review summarizes new insights based on the interaction of mitoenergetic failure, glutamate excitotoxicity, and amyloid toxicity in the exacerbation of AD. bioenergetics; synaptic dysfunction; neurodegeneration; nicotinamide adenine dinucleotide; free radicals; mitochondrial membrane potential     

Matrix alkalinization: a novel mitochondrial signal for sustained pancreatic β‐cell activation

Nutrient secretagogues activate mitochondria of the pancreatic β‐cell through the provision of substrate, hyperpolarisation of the inner mitochondrial membrane and mitochondrial calcium rises. We report that mitochondrial matrix pH, a parameter not previously studied in the β‐cell, also exerts an important control function in mitochondrial metabolism. During nutrient stimulation matrix pH alkalinises, monitored by the mitochondrial targeted fluorescent pH‐sensitive protein mtAlpHi or ³¹P‐NMR inorganic phosphate chemical shifts following saturation transfer. Compared with other cell types, the resting mitochondrial pH was surprisingly low, rising from pH 7.25 to 7.7 during nutrient stimulation of rat β‐cells. As cytosolic alkalinisation to the nutrient was of much smaller amplitude, the matrix alkalinisation was accompanied by a pronounced increase of the ΔpH across the inner mitochondrial membrane. Furthermore, matrix alkalinisation closely correlates with the cytosolic ATP net increase, which is also associated with elevated ATP synthesis rates in mitochondria. Preventing ΔpH increases in permeabilised cells abrogated substrate‐driven ATP synthesis. We propose that the mitochondrial pH and ΔpH are key determinants of mitochondrial energy metabolism and metabolite transport important for cell activation.     

Aging process modulates nonlinear dynamics in liver cell metabolism

Regulatory dynamics of energy metabolism in living cells entails a coordinated response of multiple enzyme networks that operate under non-equilibrium conditions. Here we show that mitochondrial dysfunctions associated with the aging process significantly modify nonlinear dynamical signatures in free radical generation/removal, thereby altering energy metabolism in liver cells. We support our data with a plausible biochemical mechanism for modified bioenergetics that involves uncoupling protein-2 that is up-regulated in aged cells as an adaptive response to mitigate increased oxidative stress. Combining high spatial and temporal resolution imaging and bio-energetic measurements, our work provides experimental support to the hypothesis that mitochondria manifest nonlinear dynamical behavior for efficiently regulating energy metabolism in intact cells, and any partial or complete reduction in this behavior would contribute to organ dysfunctions including the aging process and other disease processes.     

Oxidative phosphorylation and its coupling to mitochondrial creatine and adenylate kinases in human gastric mucosa

Energy metabolism in gastrobiopsy specimens of the antral and corpus mucosa, treated with saponin to permeabilize the cells, was studied in patients with gastric diseases. The results show twice lower oxidative capacity in the antral mucosa than in the corpus mucosa and the relative deficiency of antral mitochondria in complex I. The mucosal cells expressed mitochondrial and cytosolic isoforms of creatine kinase and adenylate kinase (AK). Creatine (20 mM) and AMP (2 mM) markedly stimulated mitochondrial respiration in the presence of submaximal ADP or ATP concentrations, and creatine reduced apparent Km for ADP in stimulation of respiration, which indicates the functional coupling of mitochondrial kinases to oxidative phosphorylation. Addition of exogenous cytochrome c increased ADP-dependent respiration, and the large-scale cytochrome c effect (>or=20%) was associated with suppressed stimulation of respiration by creatine and AMP in the mucosal preparations. These results point to the impaired mitochondrial outer membrane, probably attributed to the pathogenic effects of Helicobacter pylori. Compared with the corpus mucosa, the antral mucosa exhibited greater sensitivity to such type of injury as the prevalence of the large-scale cytochrome c effect was twice higher among the latter specimens. Active chronic gastritis was associated with decreased respiratory capacity of the corpus mucosa but with its increase in the antral mucosa. In conclusion, human gastric mucosal cells express the mitochondrial and cytosolic isoforms of CK and AK participating in intracellular energy transfer systems. Gastric mucosa disease is associated with the altered functions of these systems and oxidative phosphorylation.     

Implication of liver cardiolipins in mitochondrial energy metabolism disorder in cancer cachexia

Mitochondrial membranes are essential for the good functioning of the organelle. For instance, the inner mitochondrial membrane contains the oxidative phosphorylation system that permits ATP synthesis. Phospholipids environment and especially cardiolipin are crucial for the mitochondrial energy metabolism. Indeed, cardiolipin is known to provide essential structural and functional support to several proteins involved in oxidative phosphorylation. Alterations in cardiolipin structure, content and fatty acids composition have been associated with mitochondrial dysfunction in several physiopathological conditions and diseases. Cancer cachexia is a complex and dynamic process characterized by a negative energy balance induced by anorexia and hypermetabolism which leads to a drastic loss in body weight that aggravate prognosis of cancer patients. The underlying mechanisms of hypermetabolism are not fully understood. Whether the mitochondrial energy metabolism is altered during this disease and may participate to hypermetabolism is not clear. This mini-review focuses on cardiolipin especially its biosynthesis and remodeling pathways, its relation with mitochondrial energy metabolism and its possible implication in the cancer cachexia syndrome.     

Quantitative studies of enzyme-substrate compartmentation,functional coupling and metabolic channelling in muscle cells

Some historical aspects of development of the concepts of functional coupling, metabolic channelling, compartmentation and energy transfer networks are reviewed. Different quantitative approaches, including kinetic and mathematical modeling of energy metabolism, intracellular energy transfer and metabolic regulation of energy production and fluxes in the cells in vivo are analyzed. As an example of the system with metabolic channelling, thermodynamic aspects of the functioning the mitochondrial creatine kinase functionally coupled to the oxidative phosphorylation are considered. The internal thermodynamics of the mitochondrial creatine kinase reaction is similar to that for other isoenzymes of creatine kinase, and the oxidative phosphorylation process specifically influences steps of association and dissociation of MgATP with the enzyme due to channelling of ATP from adenine nucleotide translocase. A new paradigm of muscle bioenergetics - the paradigm of energy transfer and feedback signaling networks based on analysis of compartmentation phenomena and structural and functional interactions in the cell is described. Analysis of the results of mathematical modeling of the compartmentalized energy transfer leads to conclusion that both calcium and ADP, which concentration changes synchronously in contraction cycle, may simultaneously activate oxidative phosphorylation in the muscle cells in vivo. The importance of the phosphocreatine circuit among other pathways of intracellular energy transfer network is discussed on the basis of the recent data published in the literature, with some experimental demonstration. The results of studies of perfused rat hearts with completely inhibited creatine kinase show significantly decreased work capacity and respectively, energy fluxes, in these hearts in spite of significant activation of adenylate kinase system (Dzeja et al. this volume). These results, combined with those of mathematical analysis of the energy metabolism of hearts of transgenic mice with switched off creatine kinase isoenzymes confirm the importance of phosphocreatine pathway for energy transfer for cell function and energetics in mature heart and many other types of cells, as one of major parts of intracellular energy transfer network and metabolic regulation.     

Regulation of respiration in muscle cells in vivo by VDAC through interaction with the cytoskeleton and MtCK within Mitochondrial Interactosome

This review describes the recent experimental data on the importance of the VDAC-cytoskeleton interactions in determining the mechanisms of energy and metabolite transfer between mitochondria and cytoplasm in cardiac cells. In the intermembrane space mitochondrial creatine kinase connects VDAC with adenine nucleotide translocase and ATP synthase complex, on the cytoplasmic side VDAC is linked to cytoskeletal proteins. Applying immunofluorescent imaging and Western blot analysis we have shown that β2-tubulin coexpressed with mitochondria is highly important for cardiac muscle cells mitochondrial metabolism. Since it has been shown by Rostovtseva et al. that αβ-heterodimer of tubulin binds to VDAC and decreases its permeability, we suppose that the β-tubulin subunit is bound on the cytoplasmic side and α-tubulin C-terminal tail is inserted into VDAC. Other cytoskeletal proteins, such as plectin and desmin may be involved in this process. The result of VDAC-cytoskeletal interactions is selective restriction of the channel permeability for adenine nucleotides but not for creatine or phosphocreatine that favors energy transfer via the phosphocreatine pathway. In some types of cancer cells these interactions are altered favoring the hexokinase binding and thus explaining the Warburg effect of increased glycolytic lactate production in these cells. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.     

Miro1: New wheels for transferring mitochondria

Mesenchymal stem cells (MSC) are capable of protecting cells harboring mitochondrial damage. This protection is associated with the transfer of mitochondria through tunneling nanotubes (TNT) from MSC to the injured cells. In this issue of The EMBO Journal, the group of Anurag Agrawal shows that mitochondrial transfer is dependent on the levels of Miro1, a mitochondrial Rho‐GTPase that regulates intercellular mitochondrial movement. Miro1 is the first protein shown to accelerate mitochondrial transfer. Amplifying the mitochondrial transfer phenomenon may allow for the study of the mechanisms that regulate it and contribute to our understanding of its role in disease and aging.     

Profiling of mitochondrial associated proteins from rat colon

Mitochondrial dysfunction, damage and mutations of mitochondrial proteins give rise to a range of ill understood patterns of disease. Although there is significant general knowledge of the proteins and the functional processes of the mitochondria, there is little knowledge of difference about how mitochondria respond and how they are regulated in different organs and tissues. Proteomic profiling of mitochondria and associated proteins involved in mitochondrial regulation and trafficking within cells and tissues has the potential to provide insights into mitochondrial dysfunction associated with many human diseases. The rat colon mitoproteome analysis presented here provides a useful tool to assist in identification and interpretation of mitochondrial dysfunction implicated in colon pathogenesis. 2DPAGE followed by LC/MS/MS was used to identify 430 proteins from mitochondrial enriched fractions prepared from rat colon, resulting in 195 different proteins or approximately 50% of the resolved proteins being identified as multiple protein expression forms. Proteins associated with the colon mitoproteome were involved in calcium binding, cell cycle, energy metabolism and electron transport chain, protein folding, protein synthesis and degradation, redox regulation, structural proteins, signalling and transporter and channel proteins. The mitochondrial associated proteins identified in this study of colon tissue complement and are compared with other recently published mitoproteome analyses from other organ tissues, and will assist in revealing potentially organ specific roles of the mitochondria and organ specific disease associated with mitochondrial dysfunction.     

The role of mitochondrial cardiolipin in heart function and its implication in cardiac disease

Mitochondria play an essential role in the energy metabolism of the heart. Many of the essential functions are associated with mitochondrial membranes and oxidative phosphorylation driven by the respiratory chain. Mitochondrial membranes are unique in the cell as they contain the phospholipid cardiolipin. The important role of cardiolipin in cardiovascular health is highlighted by several cardiac diseases, in which cardiolipin plays a fundamental role. Barth syndrome, Sengers syndrome, and Dilated cardiomyopathy with ataxia (DCMA) are genetic disorders, which affect cardiolipin biosynthesis. Other cardiovascular diseases including ischemia/reperfusion injury and heart failure are also associated with changes in the cardiolipin pool. Here, we summarize molecular functions of cardiolipin in mitochondrial biogenesis and morphology. We highlight the role of cardiolipin for the respiratory chain, metabolite carriers, and mitochondrial metabolism and describe links to apoptosis and mitochondria specific autophagy (mitophagy) with possible implications in cardiac disease.