Vimentin intermediate filaments increase mitochondrial membrane potential

Mitochondria are the main source of energy in eukaryotic cells. They also play an important role in the number of other processes, such as regulation of calcium concentration and sequestration of apoptotic factors. Almost all functions of mitochondria depend on their ability to generate and maintain membrane potential by means of aerobic respiration. The level of mitochondrial potential is under the control of different inner and outer factors. However, mechanisms of this regulation are still poorly understood. In the present study we answer the question of how membrane potential of mitochondria depends on their motility. Using the potential-dependent dye MitoTracker Red, fluorescent microscopy of live cells, and the analysis of mitochondrial motility, two sub-populations of mitochondria were determined: (1) moving mitochondria transported along microtubules and (2) stationary mitochondria. We have shown that stationary mitochondria have higher membrane potential than moving mitochondria. It was also found that the level of potential of mitochondria is regulated by their interaction with vimentin intermediate filaments.     

Mitochondrial behaviour,morphology, and animal performance

We have a limited understanding of the proximate mechanisms that are responsible for the development of variation in animal performance and life‐history strategies. Provided that components of an organism's successful life history – for example, mate competition, gestation, lactation, etc. – are energetically demanding, increased energy production within mitochondria is likely the foundation from which organisms are able to perform these tasks. Mitochondrial behaviour (positioning within the cell and communication between mitochondria) and morphology affect variation in energy production at the molecular, cellular, and organismal levels. Therefore, adaptations in mitochondrial behaviour and morphology that favour efficient energy production likely influence variation in animal performance. Previous work has linked greater proportions of inter‐mitochondrial junctions and density of the inner mitochondrial membrane, among other traits, with increased energetic demand. Future research should focus on how inter‐mitochondrial junctions and morphology of the inner mitochondrial membrane, in particular, influence animal performance in accordance with mitochondrial density, fission, and fusion.     

Mitochondrial function in immune cells in health and disease

One of the main functions of mitochondria is production of ATP for cellular energy needs, however, it becomes more recognized that mitochondria are involved in differentiation and activation processes of immune cells. Upon activation, immune cells have a high need for energy. Immune cells have different strategies to generate this energy. In pro-inflammatory cells, such as activated monocytes and activated T and B cells, the energy is generated by increasing glycolysis, while in regulatory cells, such as regulatory T cells or M2 macrophages, energy is generated by increasing mitochondrial function and beta-oxidation.Except for being important for energy supply during activation, mitochondria also induce immune responses. During an infection, they release mitochondrial danger associated molecules (DAMPs) that resemble structures of bacterial derived pathogen associated molecular patterns (PAMPs). Such mitochondrial DAMPS are for instance mitochondrial DNA with hypomethylated CpG motifs or a specific lipid that is only present in prokaryotic bacteria and mitochondria, i.e. cardiolipin. Via release of such DAMPs, mitochondria guide the immune response towards an inflammatory response against pathogens. This is an important mechanism in early detection of an infection and in stimulating and sustaining immune responses to fight infections. However, mitochondrial DAMPs may also have a negative impact. If mitochondrial DAMPs are released by damaged cells, without the presence of an infection, such as after a trauma, mitochondrial DAMPs may induce an undesired inflammatory response, resulting in tissue damage and organ dysfunction. Thus, immune cells have developed mechanisms to prevent such undesired immune activation by mitochondrial components.In the present narrative review, we will describe the current view of mitochondria in regulation of immune responses. We will also discuss the current knowledge on disturbed mitochondrial function in immune cells in various immunological diseases.     

Denitrosylate and live longer: how ADH5/GSNOR links mitophagy to aging

Mitochondrial dynamics is required to adapt the manifold functions of mitochondria to cell needs and regulate their turnover by mitophagy. Actually, only if fragmented, mitochondria are engulfed by phagophores, the precursors to autophagosomes, and subsequently degraded. This process is essential to maintain a correct and healthy number of mitochondria that, otherwise, might be harmful. They, indeed, represent the main source of reactive oxygen species that – according to the mitochondrial free radical theory of aging – can cause aging when chronically overproduced. In a recent study, we demonstrated that S-nitrosylation, the reversible modification of cysteine residues by nitric oxide (NO), hyperactivates mitochondrial fragmentation by targeting DNM1L/Drp1 (dynamin 1-like) at Cys644, but inhibits mitophagy, the concomitant occurrence of these conditions driving cell senescence. We demonstrated that cell senescence, as well as mouse and human aging are characterized by an epigenetically-driven decrease in ADH5/GSNOR (alcohol dehydrogenase 5 [class III], chi polypeptide), suggesting that ADH5 may act as new longevity gene.     

Role of complex II in anaerobic respiration of the parasite mitochondria from Ascaris suum and Plasmodium falciparum.

Parasites have developed a variety of physiological functions necessary for existence within the specialized environment of the host. Regarding energy metabolism, which is an essential factor for survival, parasites adapt to low oxygen tension in host mammals using metabolic systems that are very different from that of the host. The majority of parasites do not use the oxygen available within the host, but employ systems other than oxidative phosphorylation for ATP synthesis. In addition, all parasites have a life cycle. In many cases, the parasite employs aerobic metabolism during their free-living stage outside the host. In such systems, parasite mitochondria play diverse roles. In particular, marked changes in the morphology and components of the mitochondria during the life cycle are very interesting elements of biological processes such as developmental control and environmental adaptation. Recent research has shown that the mitochondrial complex II plays an important role in the anaerobic energy metabolism of parasites inhabiting hosts, by acting as quinol-fumarate reductase.     

Dynamic organization of mitochondria in human heart and in myocardial disease

Heart mitochondria, which, depending on their location within cardiomyofibers, are classified as either subsarcolemmal or interfibrillar, are the major sources of the high energy compound, adenosine triphosphate. Physiological differences between these two populations are reflected by differences in the morphology of their cristae, with those of subsarcolemmal mitochondria being mostly lamelliform, and those of interfibrillar mitochondria being mostly tubular. What determines the configuration of cristae, not only in cardiac mitochondria but in mitochondria in general, is unclear. The morphology of cardiac mitochondria, as well as their physiology, is responsive to the exigencies posed by a large variety of pathological situations. Giant cardiac mitochondria make an appearance in certain types of cardiomyopathy and as a result of dietary, pharmacological, and toxicological manipulation; such megamitochondria probably arise by a combination of fusion and true growth. Some of these enlarged organelles occasionally contain a membrane-bound deposit of β-glycogen. Those giant mitochondria induced by experimental treatment usually can be restored to normal dimensions simply by supplying the missing nutrient or by deleting the noxious substance. In some conditions, such as endurance training and ischemia, the mitochondrial matrices become pale. Dense rods or plates are present in the outer compartment of mitochondria under certain conditions. Biochemical alterations in cardiac mitochondria appear to be important in heart failure. In aging, only interfibrillar mitochondria exhibit such changes, with the subsarcolemmal mitochondria unaffected. In certain heart afflictions, biochemical defects are not accompanied by obvious morphological transformations. Mitochondria clearly play a cardinal role in homeostasis of the heart.     

Effect of cyanide on mitochondrial membrane depolarization induced by uncouplers

In this work, it was found that the ability of common uncouplers – carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP) and 2,4-dinitrophenol (DNP) – to reduce membrane potential of isolated rat liver mitochondria was diminished in the presence of millimolar concentrations of the known cytochrome c oxidase inhibitor – cyanide. In the experiments, mitochondria were energized by addition of ATP in the presence of rotenone, inhibiting oxidation of endogenous substrates via respiratory complex I. Cyanide also reduced the uncoupling effect of FCCP and DNP on mitochondria energized by succinate in the presence of ferricyanide. Importantly, cyanide did not alter the protonophoric activity of FCCP and DNP in artificial bilayer lipid membranes. The causes of the effect of cyanide on the efficiency of protonophoric uncouplers in mitochondria are considered in the framework of the suggestion that conformational changes of membrane proteins could affect the state of lipids in their vicinity. In particular, changes in local microviscosity and vacuum permittivity could change the efficiency of protonophore-mediated translocation.     

Quantitative Proteomics of Presynaptic Mitochondria Reveal an Overexpression and Biological Relevance of Neuronal MitoNEET in Postnatal Brain Development

Although it has been recognized that energy metabolism and mitochondrial structure and functional activity in the immature brain differs from that of the adult, few studies have examined mitochondria specifically at the neuronal synapse during postnatal brain development. In this study, we examined the presynaptic mitochondrial proteome in mice at postnatal day 7 and 42, a period that involves the formation and maturation of synapses. Application of two independent quantitative proteomics approaches – SWATH‐MS and super‐SILAC – revealed a total of 40 proteins as significantly differentially expressed in the presynaptic mitochondria. In addition to elevated levels of proteins known to be involved in ATP metabolic processes, our results identified increased levels of mitoNEET (Cisd1), an iron‐sulfur containing protein that regulates mitochondrial bioenergetics. We found that mitoNEET overexpression plays a cell‐type specific role in ATP synthesis and in neuronal cells promotes ATP generation. The elevated ATP levels in SH‐SY5Y neuroblastoma cells were associated with increased mitochondrial membrane potential and a fragmented mitochondrial network, further supporting a role for mitoNEET as a key regulator of mitochondrial function.     

Mitochondrial respiratory chain dysfunction: implications in neurodegeneration

For decades mitochondria have been considered static round-shaped organelles in charge of energy production. In contrast, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival, because of their role in the modulation of apoptosis, autophagy, and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions and the implication of mitochondrial dysfunction in multifactorial human pathologies such as cancer, Alzheimer and Parkinson diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields for exploring the roles of these mitochondrial pathways in human pathologies. This review dissects the relationships between activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus on their implications for neurodegeneration.     

Mitochondrial contact sites as platforms for phospholipid exchange

Mitochondria are unique organelles that contain their own – although strongly reduced – genome, and are surrounded by two membranes. While most cellular phospholipid biosynthesis takes place in the ER, mitochondria harbor the whole spectrum of glycerophospholipids common to biological membranes. Mitochondria also contribute to overall phospholipid biosynthesis in cells by producing phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. Considering these features, it is not surprising that mitochondria maintain highly active exchange of phospholipids with other cellular compartments. In this contribution we describe the transport of phospholipids between mitochondria and other organelles, and discuss recent developments in our understanding of the molecular functions of the protein complexes that mediate these processes. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.     

Regulation of plasma membrane calcium fluxes by mitochondria

The role of mitochondria in cell signaling is becoming increasingly apparent, to an extent that the signaling role of mitochondria appears to have stolen the spotlight from their primary function as energy producers. In this chapter, we will review the ionic basis of calcium handling by mitochondria and discuss the mechanisms that these organelles use to regulate the activity of plasma membrane calcium channels and transporters.     

Sperm proteomics: potential impact on male infertility treatment

Spermatozoa are unique cells that have highly compact DNA, motility (and hypermotility) patterns, a specific morphology, localized mitochondria and an apical acrosome. They are the end product of a dynamic process termed spermatogenesis. Sperm are therefore produced with specific proteins in order to effect different traits, such as the presence of cysteine-rich protamines in DNA, which effectively compacts DNA. Moreover, specific proteins are transferred during epididymal maturation and after ejaculation in order to render sperm capable of undergoing post-ejaculatory alterations, generally termed capacitation, which confers capacity to fertilize a mature oocyte. In addition, sperm exhibit several post-translational modifications, which are fundamental to their function, such as SUMOylation and ubiquitination. Discussed in this review is the current knowledge of the sperm proteome in terms of its composition and the function that these proteins determine, as well as their post-translational modifications and how these alter sperm functional integrity. Studies are emphasized that focus on shotgun proteomics – untargeted determination of the protein constituent of a cell in a given biological condition – and technologies currently applied toward that end are reviewed.     

哺乳动物线粒体遗传和在体细胞克隆胚胎中的命运

线粒体是哺乳动物重要的细胞器之一,为细胞的生命活动提供能量.线粒体是除细胞核外唯一含有功能性基因组DNA的细胞器.由于线粒体在哺乳动物早期胚胎的发育中有多方面重要的作用,因此线粒体对体细胞克隆胚胎发育的影响成为体细胞克隆动物研究的热点.就线粒体的结构特点和遗传特性及其在同种、异种动物克隆早期胚胎发育过程中的命运以及可能的遗传机制进行综述.同时,也将比较注射异源线粒体后,线粒体在注射胚胎中的发育命运.     

线粒体在神经元程序性死亡中的作用新进展

神经元的死亡是许多神经系统疾病如阿尔茨海默病、帕金森病、急性青光眼等发生发展过程中的重要事件,传统认为,细胞死亡有凋亡、自噬、坏死三种方式,凋亡和自噬为程序性的细胞死亡,坏死为非程序性的死亡途径。而近年来的研究发现了一种名为程序性坏死(necroptosis)的可调控的坏死,因此,对这些可调控的细胞死亡的研究对治疗这类神经系统疾病有重要的意义。大量研究发现,在能量代谢和自由基代谢中占据着重要地位的线粒体在细胞死亡过程中也发挥重要作用。本文对线粒体在神经元凋亡、自噬和程序性坏死中的生物学作用的最新进展做一综述。     

Mitochondrial content is central to nuclear gene expression: Profound implications for human health

We review a recent paper in Genome Research by Guantes et al. showing that nuclear gene expression is influenced by the bioenergetic status of the mitochondria. The amount of energy that mitochondria make available for gene expression varies considerably. It depends on: the energetic demands of the tissue; the mitochondrial DNA (mtDNA) mutant load; the number of mitochondria; stressors present in the cell. Hence, when failing mitochondria place the cell in energy crisis there are major effects on gene expression affecting the risk of degenerative diseases, cancer and ageing. In 2015 the UK parliament approved a change in the regulation of IVF techniques, allowing “Mitochondrial replacement therapy” to become a reproductive choice for women at risk of transmitting mitochondrial disease to their children. This is the first time that this technique will be available. Therefore understanding the interaction between mitochondria and the nucleus has never been more important.     

The mitochondrion as Janus Bifrons

The signaling function of mitochondria is considered with a special emphasis on their role in the regulation of redox status of the cell, possibly determining a number of pathologies including cancer and aging. The review summarizes the transport role of mitochondria in energy supply to all cellular compartments (mitochondria as an electric cable in the cell), the role of mitochondria in plastic metabolism of the cell including synthesis of heme, steroids, iron-sulfur clusters, and reactive oxygen and nitrogen species. Mitochondria also play an important role in the Ca(2+)-signaling and the regulation of apoptotic cell death. Knowledge of mechanisms responsible for apoptotic cell death is important for the strategy for prevention of unwanted degradation of postmitotic cells such as cardiomyocytes and neurons.     

Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle

Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.     

Mitochondria,spermatogenesis and male infertility

Mitochondria and its role in male reproduction has remained an enigma since long. Similarly, etiology of male infertility in a large percentage of individuals, mainly primary infertility, has evaded concrete conclusions. Oxidative metabolism, energy production and free radical generation are the principal biological reactions occurring inside mitochondria. In addition to the above, mitochondria participates in an important process of apoptosis. Mitochondrial causes of infertility have triggered interest because of its presence in the tail of sperm and immense need of energy for sperm motility. Several studies on mitochondria have strongly suggested its role in fertility, some of which support mitochondrial role presenting numerous hypotheses, whereas others deny its very existence as a causative factor. We have, in the present review of existing literature, covered the role of mitochondria right from spermatogenesis to male infertility.     

Role of mitochondrial Ca2+ in the regulation of cellular energetics

Calcium is an important signaling molecule involved in the regulation of many cellular functions. The large free energy in the Ca(2+) ion membrane gradients makes Ca(2+) signaling inherently sensitive to the available cellular free energy, primarily in the form of ATP. In addition, Ca(2+) regulates many cellular ATP-consuming reactions such as muscle contraction, exocytosis, biosynthesis, and neuronal signaling. Thus, Ca(2+) becomes a logical candidate as a signaling molecule for modulating ATP hydrolysis and synthesis during changes in numerous forms of cellular work. Mitochondria are the primary source of aerobic energy production in mammalian cells and also maintain a large Ca(2+) gradient across their inner membrane, providing a signaling potential for this molecule. The demonstrated link between cytosolic and mitochondrial Ca(2+) concentrations, identification of transport mechanisms, and the proximity of mitochondria to Ca(2+) release sites further supports the notion that Ca(2+) can be an important signaling molecule in the energy metabolism interplay of the cytosol with the mitochondria. Here we review sites within the mitochondria where Ca(2+) plays a role in the regulation of ATP generation and potentially contributes to the orchestration of cellular metabolic homeostasis. Early work on isolated enzymes pointed to several matrix dehydrogenases that are stimulated by Ca(2+), which were confirmed in the intact mitochondrion as well as cellular and in vivo systems. However, studies in these intact systems suggested a more expansive influence of Ca(2+) on mitochondrial energy conversion. Numerous noninvasive approaches monitoring NADH, mitochondrial membrane potential, oxygen consumption, and workloads suggest significant effects of Ca(2+) on other elements of NADH generation as well as downstream elements of oxidative phosphorylation, including the F(1)F(O)-ATPase and the cytochrome chain. These other potential elements of Ca(2+) modification of mitochondrial energy conversion will be the focus of this review. Though most specific molecular mechanisms have yet to be elucidated, it is clear that Ca(2+) provides a balanced activation of mitochondrial energy metabolism that exceeds the alteration of dehydrogenases alone.