The missing link between hydrogenosomes and mitochondria

Mitochondria typically respire oxygen and possess a small DNA genome. But among various groups of oxygen-shunning eukaryotes, typical mitochondria are often lacking, organelles called hydrogenosomes being found instead. Like mitochondria, hydrogenosomes are surrounded by a double-membrane, produce ATP and sometimes even have cristae. In contrast to mitochondria, hydrogenosomes produce molecular hydrogen through fermentations, lack cytochromes and usually lack DNA. Hydrogenosomes do not fit into the conceptual mold cast by the classical endosymbiont hypothesis about the nature of mitochondria. Accordingly, ideas about their evolutionary origins have focussed on the differences between the two organelles instead of their commonalities. Are hydrogenosomes fundamentally different from mitochondria, the result of a different endosymbiosis? Or are our concepts about the mitochondrial archetype simply too narrow? A new report has uncovered DNA in the hydrogenosomes of anaerobic ciliates. The sequences show that these hydrogenosomes are, without a doubt, mitochondria in the evolutionary sense, even though they differ from typical mitochondria in various biochemical properties. The new findings are a benchmark for our understanding of hydrogenosome origins.     

The link between segregation and phylogenetic diversity

We derive an invertible transform linking two widely used measures of species diversity: phylogenetic diversity and the expected proportions of segregating (non-constant) sites. We assume a bi-allelic (two-state), symmetric, finite site model of substitution. Like the Hadamard transform of Hendy and Penny, the transform can be expressed independently of the underlying phylogeny. Our results bridge work on diversity from two quite distinct scientific communities.     

The link between the metabolic syndrome and cancer

Since the incidence of the metabolic syndrome is on the rise in the western world, its coherence to cancer is becoming more apparent. In this review we discuss the different potential factors involved in the increase of cancer in the metabolic syndrome including obesity, dyslipidemia and Type 2 Diabetes Mellitus (T2DM) as well as inflammation and hypoxia. We especially focus on the insulin and IGF systems with their intracellular signaling cascades mediated by different receptor subtypes, and suggest that they may play major roles in this process. Understanding the mechanisms involved will be helpful in developing potential therapeutics.     

The neurobiological context of autism

Autistic disorder (AD) is a complex neuropsychiatric disorder of neurodevelopmental origin, where multiple genetic and environmental factors may interact, resulting in a clinical continuum. The genetic component is best described by a multilocus model that takes into account epistatic interactions between several susceptibility genes. In the past ten years enormous progress has been made in identifying chromosomal regions in linkage with AD, but moving from chromosomal regions to candidate genes has proven to be tremendously difficult. Neuroanatomical findings point to early dysgenetic events taking place in the cerebral cortex, cerebellum, and brainstem. At the cellular level, disease mechanisms may include altered cell migration, increased cell proliferation, decreased cell death, or altered synapse elimination. Neurochemical findings in AD point to involvement of multiple neurotransmitter systems. The serotoninergic system has been intensively investigated in AD, but other neurotransmitter systems (e.g., the GABAergic and the cholinergic system) are also coming under closer scrutiny. The role of environmental factors is still poorly characterized. It is not clear yet whether environmental factors act merely as precipitating agents, always requiring an underlying genetic liability, or whether they represent an essential component of a pathogenetic process where genetic liability alone does not lead to the full-blown autism phenotype. A third potential player in the pathogenesis of autism, in addition to genetic and environmental factors, is developmental variability due to “random” factors, e.g. small fluctuations of gene expression and complex, non-deterministic interactions between genes during brain development. These considerations suggest that a non-deterministic conceptual framework is highly appropriate for autism research.     

The link between physics and chemistry in track modelling

The physical structure of a radiation track provides the initial conditions for the modelling of radiation chemistry. These initial conditions are not perfectly understood, because there are important gaps between what is provided by a typical track structure model and what is required to start the chemical model. This paper addresses the links between the physics and chemistry of tracks, with the intention of identifying those problems that need to be solved in order to obtain an accurate picture of the initial conditions for the purposes of modelling chemistry. These problems include the reasons for the increased yield of ionisation relative to homolytic bond breaking in comparison with the gas phase. A second area of great importance is the physical behaviour of low-energy electrons in condensed matter (including thermolisation and solvation). Many of these processes are not well understood, but they can have profound effects on the transient chemistry in the track. Several phenomena are discussed, including the short distance between adjacent energy loss events, the molecular nature of the underlying medium, dissociative attachment resonances and the ability of low-energy electrons to excite optically forbidden molecular states. Each of these phenomena has the potential to modify the transient chemistry substantially and must therefore be properly characterised before the physical model of the track can be considered to be complete. Received: 15 March 1999 / Accepted in revised form: 29 July 1999     

Pattern Formation: The link between ovary and embryo

The Drosophila gene nudel may encode a spatially restricted serine protease involved in producing the ligand for the receptor Toll and linking dorsal–ventral polarity in the egg chamber to the developing embryonic axis.     

恐惧记忆消散的神经生物学机制研究进展

恐惧消散被认为是一种通过形成新的抑制性学习来拮抗最初的恐惧记忆的复杂过程。目前,通过旨在促进恐惧消散的疗法治疗诸如焦虑症等神经精神疾病已在临床上取得了较好的疗效,因此,如何更有效持久地维持恐惧消散记忆具有重要的意义。围绕与恐惧记忆消散相关的脑区及恐惧记忆消散的分子机制进行阐述,有助于更深入地理解恐惧记忆消散相关的神经生物学机制,为后续研究提供新的方向。     

The vesicular ATPase: A missing link between acidification and exocytosis

The vesicular adenosine triphosphatase (ATPase) acidifies intracellular compartments, including synaptic vesicles and secretory granules. A controversy about a second function of this ATPase in exocytosis has been fuelled by questions about multiple putative roles of acidification in the exocytic process. Now, Poëa-Guyon et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201303104) present new evidence that the vesicular ATPase performs separate acidification and exocytosis roles and propose a mechanism for how these two functions are causally linked.Vesicular H⁺-ATPases (V-ATPases) function as ATP-driven proton pumps in intracellular compartments, such as endosomes, Golgi-derived vesicles, secretory vesicles, synaptic vesicles, lysosomes, and vacuoles (Forgac, 2007). Acidification is important for a plethora of cell biological processes ranging from endosomal ligand–receptor dissociation to lysosomal degradation (Yan et al., 2009; Williamson et al., 2010; Zoncu et al., 2011). Consequently, interfering with V-ATPase function leads to direct and indirect defects that are difficult to tease apart. In addition, acidification-independent roles of the V-ATPase in secretion and membrane fusion have been proposed (Israël et al., 1986; Peters et al., 2001; Morel et al., 2003; Hiesinger et al., 2005; Liégeois et al., 2006; Sun-Wada et al., 2006; Peri and Nüsslein-Volhard, 2008). The difficulty to distinguish consequences of an acidification-independent mechanism from indirect effects of acidification defects is exacerbated by an unclear dependence of secretion on acidification (Cousin and Nicholls, 1997; Ungermann et al., 1999; Hiesinger et al., 2005).In synaptic vesicles, the V-ATPase generates a proton gradient that is used by an antiporter to fill synaptic vesicles with neurotransmitter. Hence, loss of acidification leads to “empty” synaptic vesicles and loss of neurotransmitter release. Can such vesicles still fuse and thereby “shoot blanks”? The V-ATPase comprises of two sectors that can reversibly dissociate: the cytosolic V1 sector and the membrane-bound V0 sector. Loss of the neuronal a1 subunit of the V0 sector (V0a1) leads to almost complete loss of neurotransmission in Drosophila melanogaster—a phenotype that may result from a defect in neurotransmitter loading or exocytosis (Hiesinger et al., 2005). Single vesicle release events in the V0a1 mutant revealed a quantal postsynaptic response, suggesting that at least some vesicles are loaded. In addition, loss of V0a1 impairs synaptic vesicle cycling in an FM1-43 dye uptake assay, whereas pharmacological block of the V-ATPase with bafilomycin causes no significant defect in this assay (Hiesinger et al., 2005). These findings supported previous studies of an acidification-independent role of the yeast V0 sector and specifically the V0a1 orthologue vph1 in vacuole fusion (Peters et al., 2001; Bayer et al., 2003). They also support earlier controversial implications of the V-ATPase V0 sector in neurotransmitter release (Israël et al., 1986). More recently, numerous studies have added evidence in worm, fish, fly, and mouse for possible acidification-independent roles of various V-ATPase V0 subunits in secretion or membrane fusion (Bayer et al., 2003; Lee et al., 2006; Liégeois et al., 2006; Sun-Wada et al., 2006; Peri and Nüsslein-Volhard, 2008; Di Giovanni et al., 2010; Williamson et al., 2010; Strasser et al., 2011). However, questions about the relationship of V-ATPase–dependent acidification and the observed secretion or membrane fusion defects remained. How can one cleanly separate between two protein functions if one potentially depends on the other? The study of V0a1 has been complicated by the finding that it is not only a synaptic vesicle protein but also localizes to other organelles. Consequently, specific disruption of the acidification function of V0a1 led to endolysosomal acidification defects, even though it partially restored neurotransmission (Williamson et al., 2010). A better dissection of the two possible functions is needed.In this issue of JCB, Poëa-Guyon et al. provide compelling evidence for two separable functions of V0a1 in acidification and exocytosis. Instead of a genetic dissection, they opted for an elegant temporal dissection with the idea that acute inactivation of a function of V0a1 in exocytosis should instantly block neurotransmission, whereas acute inactivation of the proton pump should leave neurotransmission functional as long as loaded vesicles are available. Indeed, Poëa-Guyon et al. (2013) found a fast disruption of secretion in both primary rat neuronal culture and chromaffin cells when they acutely inactivated V0a1 using chromophore-assisted light inactivation. In contrast, inactivation of the reversibly associated V1 sector revealed very different effects than what would be expected from a loss of the proton pump.How about the dependence of exocytosis on acidification? Poëa-Guyon et al. (2013) developed an assay based on granule exocytosis in neurosecretory PC12 cells. Compartmental proton gradients can be abolished by a variety of means, including pharmacological inhibition of the V-ATPase with bafilomycin or concanamycin. A more acute destruction of intracompartmental proton gradients can be achieved through addition of alkalizing ammonium chloride or the potassium ionophore nigericin, which exchanges intracompartmental protons with potassium ions. Interestingly, Poëa-Guyon et al. (2013) found that only the acute disruption of the intracompartmental proton gradients with ammonium chloride or nigericin leads to an impairment of secretion but not block of the V-ATPase. What happens to the V-ATPase and its acidification-independent function under these different conditions? The authors show that both ammonium chloride and nigericin not only abolish the proton gradient but also lead to increased association of the V0 and V1 sectors (Fig. 1). This association is required to form a functional pump. A straightforward explanation for this observation is that the cell attempts to activate the proton pump to reacidify vesicles that lost their proton gradient. In contrast, the pharmacological block of the V-ATPase itself leads to increased free V0 sectors, consistent with loss of proton pump function. In a key experiment, Poëa-Guyon et al. (2013) show that this pharmacological inhibition of the V-ATPase with bafilomycin can override the effects of ammonium chloride or nigericin and restore secretion. If the pharmacological block of the V-ATPase prevents V0–V1 association, no functional pumps assemble even in the presence of ammonium chloride or nigericin. This result implies that the V0–V1 association itself prevents exocytosis. Pharmacological V0–V1 dissociation seems sufficient to expose V0 and exert a V1-independent function in exocytosis. This conclusion is consistent with previous findings in which the same pharmacological inhibition of the V-ATPase was found to leave exocytosis and endocytosis intact (Cousin and Nicholls, 1997; Hiesinger et al., 2005). However, the interpretation of the data changes: according to the new findings, exocytosis does not depend on vesicle acidification, per se, but on V0–V1 association that results from lack of acidification. Acidification and V-ATPase assembly thereby become a checkpoint for vesicle loading, and the assembled V-ATPase becomes a no-go signal for fusion (Fig. 1). The model is elegant and leads Poëa-Guyon et al. (2013) to suggest the V-ATPase as an acidification sensor, similar to previous observations (Hurtado-Lorenzo et al., 2006). However, whether it is really the V-ATPase itself that senses the proton gradient is not directly assessed in this study.Open in a separate windowFigure 1.V-ATPase V0–V1 association blocks secretion. (A) Poëa-Guyon et al. (2013) suggest that dissociation of V0 (red boxes) and V1 (green cylinders) sectors follows vesicle acidification (yellow) and frees the V0 sector for an acute, acidification-independent function in secretion.(B) V-ATPase–independent pharmacological disruption of vesicular acidification causes increased V0–V1 assembly of the functional proton pump, which in turn blocks secretion.(C) Pharmacological disruption of the V-ATPase disrupts both vesicle acidification and V0–V1 assembly, thereby permitting V0-dependent secretion. This mechanism can override disruption of acidification shown in B and restores secretion of nonacidified vesicles.How general is the V-ATPase checkpoint, and what is the mechanism of V0-mediated, acidification-independent exocytosis? Both questions remain unanswered. The checkpoint idea is beautiful and does not obviously contradict current ideas on exocytic regulation. However, potential mechanisms for V0-mediated membrane fusion remain controversial (Saw et al., 2011; Ernstrom et al., 2012). In yeast, V0 proteolipid expansion in the membrane has been proposed to play a direct role in lipid mixing during vacuole fusion based on a thorough genetic dissection of fusion and acidification functions of the V0 sector (Strasser et al., 2011). No such role has hitherto been shown for neurotransmitter release, which comprises numerous different forms of vesicle release that are differentially regulated. A better genetic or pharmacological dissection is needed to reveal when, where, and how V0 meddles with membrane fusion.     

The protein Mago provides a link between splicing and mRNA localization

The proteins Mago and Y14 are evolutionarily conserved binding partners. Y14 is a component of the exon–exon junction complex (EJC), deposited by the spliceosome upstream of messenger RNA (mRNA) exon–exon junctions. The EJC is implicated in post-splicing events such as mRNA nuclear export and nonsense-mediated mRNA decay. Drosophila Mago is essential for the localization of oskar mRNA to the posterior pole of the oocyte, but the functional role of Mago in other species is unknown. We show that Mago is a bona fide component of the EJC. Like Y14, Mago escorts spliced mRNAs to the cytoplasm, providing a direct functional link between splicing and the downstream process of mRNA localization. Mago/Y14 heterodimers are essential in cultured Drosophila cells. Taken together, these results suggest that, in addition to its specialized function in mRNA localization, Mago plays an essential role in other steps of mRNA metabolism.     

The link between small heat shock proteins and the immune system

There is now compelling evidence that members of the family of small heat shock proteins (HSP) can be secreted by a variety of different types of cells. Secretion of small HSP may at times represent altruistic delivery of supporting and stabilizing factors from one cell to another. A probably more general effect of extracellular small HSP, however, is exerted by their ability to activate macrophages and macrophage-like cells. When doing so, small HSP induce an immune-regulatory state of activation, stimulating macrophages to suppress inflammation. For this reason, small HSP deserve consideration as broadly applicable therapeutic agents for inflammatory disorders. In one particular case, however, adaptive immune responses to the small HSP itself may subvert the protective quality of the innate immune response it triggers. This situation only applies to alpha B-crystallin, and is unique for humans as well. In this special case, local concentrations of alpha B-crystallin determine the balance between protective innate responses and destructive adaptive responses, the latter of which are held responsible for the development of multiple sclerosis lesions. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.