Crosstalk between mitochondria and peroxisomes

Mitochondria and peroxisomes are small ubiquitous organelles. They both play major roles in cell metabolism,especially in terms of fatty acid metabolism,reactive oxygen species(ROS) production,and ROS scavenging,and it is now clear that they metabolically interact with each other. These two organelles share some properties,such as great plasticity and high potency to adapt their form and number according to cell requirements. Their functions are connected,and any alteration in the function of mitochondria may induce changes inperoxisomal physiology. The objective of this paper was to highlight the interconnection and the crosstalk existing between mitochondria and peroxisomes. Special emphasis was placed on the best known connections between these organelles:origin,structure,and metabolic interconnections.     

Long-chain acylcarnitine content determines the pattern of energy metabolism in cardiac mitochondria

In the heart, a nutritional state (fed or fasted) is characterized by a unique energy metabolism pattern determined by the availability of substrates. Increased availability of acylcarnitines has been associated with decreased glucose utilization; however, the effects of long-chain acylcarnitines on glucose metabolism have not been previously studied. We tested how changes in long-chain acylcarnitine content regulate the metabolism of glucose and long-chain fatty acids in cardiac mitochondria in fed and fasted states. We examined the concentrations of metabolic intermediates in plasma and cardiac tissues under fed and fasted states. The effects of substrate availability and their competition for energy production at the mitochondrial level were studied in isolated rat cardiac mitochondria. The availability of long-chain acylcarnitines in plasma reflected their content in cardiac tissue in the fed and fasted states, and acylcarnitine content in the heart was fivefold higher in fasted state compared to the fed state. In substrate competition experiments, pyruvate and fatty acid metabolites effectively competed for the energy production pathway; however, only the physiological content of acylcarnitine significantly reduced pyruvate and lactate oxidation in mitochondria. The increased availability of long-chain acylcarnitine significantly reduced glucose utilization in isolated rat heart model and in vivo. Our results demonstrate that changes in long-chain acylcarnitine contents could orchestrate the interplay between the metabolism of pyruvate–lactate and long-chain fatty acids, and thus determine the pattern of energy metabolism in cardiac mitochondria.     

Morphologic effects of sulfur-substituted fatty acids on rat hepatocytes with special reference to proliferation of peroxisomes and mitochondria

The morphologic effects of different sulfur-substituted mono- and dicarboxylic fatty acids on rat hepatocytes have been examined. The substance 1,10-biscarboxymethylthiodecane (BCMTD) is blocked for both beta- and omega-oxidation, whereas 1-monocarboxymethylthiodecane (CMTTD) is only non-beta-oxidizable. At equimolar doses BCMTD was considerably more potent than CMTTD in hypertrophic liver enlargement. At the ultrastructural level, BCMTD increased the volume fraction of the peroxisomes by a factor of 8, and their size and number by factors of 2.1 and 6.4, respectively. Furthermore, the frequency of dense cores in the peroxisomes decreased from 60 to 8%. CMTTD resulted in an increased volume fraction of peroxisomes (4.5-fold), in the mean volume (1.9-fold), and in the number of peroxisomes (3.7-fold). At the mitochondrial level, a gradual development toward megamitochondria was observed after CMTTD administration. BCMTD, however, increased the number of mitochondria but they tended to be smaller. Administration of both acids increased peroxisomal beta-oxidation and mitochondrial carnitine palmitoyltransferase activity, whereas the lipid content of hepatocytes was reduced with increasing doses of CMTTD and especially BCMTD. The acid 1-mono(carboxyethylthio)tetradecane (CETTD), which is able to undergo one cycle of beta-oxidation, caused no change in liver weight, and only marginal effects on peroxisomes and mitochondria were observed. In contrast to the BCMTD and CMTTD feeding, the animals developed a tremendous accumulation of fat in the livers: the volume fraction of lipid droplets increased 23-fold after CETTD feeding.     

Metabolic defects shared by Alzheimer's disease and diabetes: A focus on mitochondria

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two global epidemics that share several metabolic defects, such as insulin resistance, impaired glucose metabolism, and mitochondrial defects. Importantly, strong evidence demonstrates that T2D significantly increases the risk of cognitive decline and dementia, particularly AD. Here, we provide an overview of the metabolic defects that characterize and link both pathologies putting the focus on mitochondria. The biomarker potential of mitochondrial components and the therapeutic potential of some drugs that target and modulate mitochondria are also briefly discussed.     

The conserved fission complex on peroxisomes and mitochondria

Peroxisomes are eukaryotic organelles highly versatile and dynamic in content and abundance. Plant peroxisomes mediate various metabolic pathways, a number of which are completed sequentially in peroxisomes and other subcellular organelles, including mitochondria and chloroplasts. To understand how peroxisomal dynamics contribute to changes in plant physiology and adaptation, the multiplication pathways of peroxisomes are being dissected. Research in Arabidopsis thaliana has identified several evolutionarily conserved families of proteins in peroxisome division. These include five PEROXIN11 proteins (PEX11a to -e) that induce peroxisome elongation and the fission machinery, which is composed of three dynamin-related proteins (DRP3A, -3B and -5B) and DRP''s membrane receptor, FISSION1 (FIS1A and -1B). While the function of PEX11 is restricted to peroxisomes, the fission factors are more promiscuous. DRP3 and FIS1 proteins are shared between peroxisomes and mitochondria, and DRP5B plays a dual role in the division of chloroplasts and peroxisomes. Analysis of the Arabidopsis genome suggests that higher plants may also contain functional homologs of the yeast Mdv1/Caf4 proteins, adaptor proteins that link DRPs to FIS1 on the membrane of both peroxisomes and mitochondria. Sharing a conserved fission machine between these metabolically linked subcellular compartments throughout evolution may have some biological significance.Key words: Arabidopsis, peroxisomal and mitochondrial division, dynamin-related protein (DRP), FISSION1 (FIS1), mitochondrial division 1 (Mdv1), CCR4p-associated factor 4 (Caf4)Peroxisomes are single membrane-delimited organelles involved in a variety of metabolic pathways essential to development.¹ Plant peroxisomes participate in processes such as lipid mobilization, photorespiration, detoxification, hormone biosynthesis and metabolism, and plant-pathogen interaction.^2,3 A number of these metabolic functions, such as photorespiration, fatty acid metabolism and jasmonic acid biosynthesis, are accomplished through the cooperative efforts of peroxisomes and other subcellular compartments, such as mitochondria and chloroplasts.^3–5 The function, morphology and abundance of peroxisomes can vary depending on the organism, cell type, developmental stage and prevailing environmental conditions in which the organism resides.^6,7 It is now believed that in addition to budding from the endoplasmic reticulum (ER), peroxisomes also multiply from pre-existing peroxisomes via division, going through steps including peroxisome elongation/tubulation, membrane constriction and fission.^7,8In the reference plant Arabidopsis thaliana, three evolutionarily conserved families of proteins have been identified as key components of the peroxisome division apparatus. Five integral membrane proteins, named PEX11a to -e, are mainly responsible for inducing the elongation and tubulation of peroxisomes in the early stage of peroxisome division.^9–11 DRP3A and DRP3B are members of a dynamin-related protein family that powers the fission of membranes and FIS1A and FIS1B are homologous proteins believed to anchor the DRP proteins to the membrane.^12–19 Similar to their counterparts in yeasts and mammals, DRP3 and FIS1 are shared by the fission machineries of peroxisomes and mitochondria.^12–19 We recently reported the unexpected finding that DRP5B, a plant/algal-specific DRP distantly related to the DRP3 proteins and originally discovered for its function in chloroplast division, is also involved in the division of peroxisomes. Using co-immunoprecipitation (co-IP) and bimolecular fluorescence complementation (BiFC) assays, we further demonstrated that DRP5B and the two DRP3 proteins can homo- and hetero-dimerize and each DRP can form a complex with FIS1A and/or FIS1B and most of the Arabidopsis PEX11 isoforms.²⁰ These results together demonstrate that, despite their distinct evolutionary origins, structures and functions, peroxisomes, mitochondria and chloroplasts use some of the same factors for fission. These data also revealed that, like in yeasts and mammals, the FIS1-DRP complex exits on peroxisomes and mitochondria in plants.DRP5B, a DRP unique in the plant and photosynthetic algae lineages, seems to be the sole component shared by the division of chloroplasts and peroxisomes.²⁰ However, both FIS1 and DRP are found to be required for the division of peroxisomes and mitochondria throughout eukaryotic evolution,^21,22 prompting the question: to what extent is the FIS1-DRP complex conserved among diverse species? In the yeast Saccharomyces cerevisiae, this fission complex also contains an adaptor encoded by two homologous WD40 proteins, Mdv1 and Caf4, which are partially redundant in function with Mdv1 playing the major role. Mdv1 and Caf4 share an N-terminal extension (NTE) domain with two α-helices, a middle coiled-coil domain (CC) and C-terminal WD40 repeat. Both proteins use the NTE to interact with the tetratricopeptide repeat (TPR) domain-containing N-terminus of Fis1, the CC domain to dimerize and the C-terminal WD40 repeat to interact with and recruit the DRP protein, Dnm1.^23,24 The Hansenula polymorpha Mdv1 (Hp Mdv1) also has a dual function in the division of peroxisomes and mitochondria.²⁵ In addition, a Mdv1/Caf4 homolog, Mda1, was identified from the primitive red algae Cyanidioschyzon merolae and found to be involved at least in mitochondrial fission.²⁶ However, higher eukaryotes do not seem to have obvious homologs of Mdv1/Caf4. For example, mammals contain Fis1 and Drp (called DLP1 or Drp1) but no apparent homologs to Mdv1 and Caf4. Instead, a metazoan-specific tail-anchored protein, Mitochondrial Fission Factor (Mff), was recently found to regulate the fission of mitochondria and peroxisomes in a similar manner to Fis1. Mff is essential in recruiting Drp1, at least in mitochondrial division, yet it functions in a Fis1-independent pathway.^27,28To determine whether plants contain structural or functional homologs of Mdv1 and Caf4, we performed blast searches of the Arabidopsis genome, which resulted in the retrieval of ∼300 WD40 proteins. However, just like the search results from mammals, none of these proteins show significant sequence similarity with Mdv1 and Caf4 beyond the WD40 repeats. To identify proteins with similar domain structures with Mdv1/Caf4, we further analyzed these WD40 proteins, using the online Simple Modular Architecture Research Tool (smart.embl-heidelberg.de/). After eliminating proteins apparently inappropriate to be part of this complex, such as kinases and proteins with drastically distinct domain organizations despite of having both WD40 repeats and CC domains, we were able to narrow down to eight proteins. These proteins, which are encoded by At1g04510, At2g32950, At2g33340, At3g18860, At4g05410, At4g21130, At5g50230 and At5g67320, respectively, each contain a central CC domain in addition to the WD40 repeat region and are ranging from 450 to 900 amino acids in length (Fig. 1A). Subcellular localization studies will need to be performed to determine whether some of these proteins are associated with peroxisomes and mitochondria. If such a WD40 protein is proven to be part of the FIS1-DRP complex in Arabidopsis, it will be important to determine whether it simply acts as an adaptor or it also plays other roles, such as to promote and maintain the active structure and conformation of DRP3A/3B at the division site (Fig. 1B). Consistent with the latter scenario, it was found that Sc Mdv1 accumulates at the division sites after Dnm1 assembles and that the mammalian Fis1 and Drp1 proteins physically interact.^29,30 Peroxisomes and mitochondria are functionally linked in a number of metabolic pathways. For example, in plants, they act cooperatively in important processes such as fatty acid metabolism and photorespiration.³ An interesting question to address in the future is whether sharing such a conserved fission machine between peroxisomes and mitochondria throughout evolution has critical biological consequences.Open in a separate windowFigure 1Domain structure of Mdv1/Caf4 and their homologs or putative homologs. (A) Domain structure of Sc Mdv1 and Sc Caf4 from S. cerevisiae, their homologs from H. polymorpha and C. merolae, and the eight Arabidopsis proteins with similar domain organization. Grey boxes indicate the CC domain and black boxes are Wd40 repeats. (B) The putative FIS1-WD40-DRP complex in Arabidopsis. CC, coiled-coil; NTE, N-terminal extension; TPR, tetratricopeptide repeat; TMD, transmembrane domain.     

Effects of essential fatty acid deficiency on mitochondria and peroxisomes in rat hepatocytes with special reference to a partially hydrogenated fish oil diet

Feeding male rats a high cal% partially hydrogenated fish oil diet induced morphological and biochemical changes in hepatocytes at the mitochondrial and peroxisomal level. At the mitochondrial level, formation of megamitochondria was related to the development of an essential fatty acid deficiency, as measured by a high 20:3/20:4 fatty acid ratio. These mitochondrial changes were fully prevented by adding linoleic acid to the partially hydrogenated fish oil diet. The megamitochondria revealed a normal specific content of respiratory chain pigments, normal specific respiratory rates and a normal energy coupling. At the peroxisomal level, feeding of the partially hydrogenated fish oil diet caused a considerable proliferation, which was unrelated to essential fatty acid deficiency. The total number of peroxisomes increased 1.9-fold, and 2.6-fold in the presence of added linoleic acid. Essential fatty acid deficiency seemed to result in an inhibition of peroxisomal biogenesis. It was concluded that the induction of megamitochondria by partially hydrogenated fish oil was fully attributable to essential fatty acid deficiency, whereas peroxisomal proliferation must be attributed to other factors in the diet.     

Physiology of pepper fruit and the metabolism of antioxidants: chloroplasts,mitochondria and peroxisomes

Background and Aims Pepper (Capsicum annuum) contains high levels of antioxidants, such as vitamins A and C and flavonoids. However, information on the role of these beneficial compounds in the physiology of pepper fruit remains scarce. Recent studies have shown that antioxidants in ripe pepper fruit play a key role in responses to temperature changes, and the redox state at the time of harvest affects the nutritional value for human consumption. In this paper, the role of antioxidant metabolism of pepper fruit during ripening and in the response to low temperature is addressed, paying particular attention to ascorbate, NADPH and the superoxide dismutase enzymatic system. The participation of chloroplasts, mitochondria and peroxisomes in the ripening process is also investigated.Scope and Results Important changes occur at a subcellular level during ripening of pepper fruit. Chloroplasts turn into chromoplasts, with drastic conversion of their metabolism, and the role of the ascorbate–glutathione cycle is essential. In mitochondria from red fruits, higher ascorbate peroxidase (APX) and Mn-SOD activities are involved in avoiding the accumulation of reactive oxygen species in these organelles during ripening. Peroxisomes, whose antioxidant capacity at fruit ripening is substantially affected, display an atypical metabolic pattern during this physiological stage. In spite of these differences observed in the antioxidative metabolism of mitochondria and peroxisomes, proteomic analysis of these organelles, carried out by 2-D electrophoresis and MALDI-TOF/TOF and provided here for the first time, reveals no changes between the antioxidant metabolism from immature (green) and ripe (red) fruits.Conclusions Taken together, the results show that investigation of molecular and enzymatic antioxidants from cell compartments, especially chloroplasts, mitochondria and peroxisomes, is a useful tool to study the physiology of pepper fruit, particularly in the context of expanding their shelf-life after harvest and in maintaining their nutritional value.     

Growth and development of children with a special focus on sleep

The first two decades of life are characterised complex biological processes involving growth and maturation as well as differentiation. The Central Nervous System (CNS) where among others internal and external stimuli are integrated and responses of the body are prepared starts to evolve quite early during ontogenesis. One of the complex behaviours, which are regulated by the brain, is the sleep-wake cycle.The discussion of age-related changes in sleep comprises changes at the physiological level (e.g. changes in the frequency and amplitude of EEG signal, as well as development and distribution of sleep stages), changes in the corresponding behaviour (e.g. changes in the absolute amount of sleep and its distribution in 24 h perspective), and finally the subjective perception of sleep and sleep as a measure of well-being.Studies on the impact of a specific factor on sleep during childhood and adolescence have to consider chronological and biological age as well as sex as relevant biological parameters. Even when these factors are controlled for large interindividual differences persist, that is why prospective instead of cross-sectional approaches should be used whenever possible. Furthermore, it has to be distinguished between sleep assessed at the level of brain functioning (i.e. by polysomnography), which gives information on effects at the physiological level and at the level of self-assessment, which focuses on behaviour. Both, sleep at the subjective as well as at the objective level, can to a considerable degree be affected by life style factors, which hence have to be considered as potential confounders.     

Nitric oxide signalling with a special focus on lipid-derived mediators

The ways in which cells communicate among each other concerns all aspects of biology, from developmental processes to diseases. Nitric oxide (NO) is one of the most remarkable and unusual regulatory molecules. It is a labile free radical gas that is not stored but generated on demand, and has been implicated in an extraordinarily diverse range of physiological and pathophysiological functions. The modulation of cell signalling by free radicals is an emerging area of research that provides insight into the orchestration of cell adaptation to a changing microenvironment. In a multicellular organism this serves to coordinate complex physiological responses, such as inflammation. Cell signalling is also accompanied by rapid remodelling of membrane lipids by activated lipases. The discovery that NO, which does not reversibly interact with membrane receptors like conventional hormones and growth factors, targets enzymes such as phospholipase A2, sphingomyelinases or ceramidases, has stimulated growing interest in the crosstalk between redox and lipid signalling.     

Metabolic interactions between cysteamine and epigallocatechin gallate

Phase II clinical trials indicate that the combination of cysteamine plus epigallocatechin gallate (EGCG) is effective against cystic fibrosis in patients bearing the most frequent etiological mutation (CFTRΔF508). Here, we investigated the interaction between both agents on cultured respiratory epithelia cells from normal and CFTRΔF508-mutated donors. We observed that the combination of both agents affected metabolic circuits (and in particular the tricarboxylic acid cycle) in a unique way and that cysteamine plus EGCG reduced cytoplasmic protein acetylation more than each of the 2 components alone. In a cell-free system, protein cross-linking activity of EGCG was suppressed by cysteamine. Finally, EGCG was able to enhance the conversion of cysteamine into taurine in metabolic flux experiments. Altogether, these results indicate that multiple pharmacological interactions occur between cysteamine and EGCG, suggesting that they contribute to the unique synergy of both agents in restoring the function of mutated CFTRΔF508.     

Association of Cu,Zn-type superoxide dismutase with mitochondria and peroxisomes

The subcellular localization of Cu,Zn-type superoxide dismutase (Cu,Zn-SOD) was investigated in rat tissues and cultured human fibroblasts. Subcellular fractionation, Nycodenz gradient centrifugation, and immunoblot analysis using specific antibodies showed that Cu,Zn-SOD was localized in cytosol, mitochondria, and peroxisomes of rat liver and brain. Treatment of highly purified mitochondria from rat liver with either Chaps or Triton X-100 released the bound Cu,Zn-SOD into supernatant fraction. Depolarization of mitochondria by inorganic phosphate and Ca(2+) released both Cu,Zn-SOD and cytochrome c from mitochondria. Digitonin also released Cu,Zn-SOD but not cytochrome c from mitochondria. Confocal immunofluorescence microscopy revealed that anti-Cu,Zn-SOD antibody in cultured human fibroblasts was found to colocalize with antibodies to Mn-SOD and PMP-70, markers of mitochondria and peroxisomes, respectively. Incubation of human Cu,Zn-SOD with purified mitochondria resulted in their association. These results indicate that Cu,Zn-SOD associates with mitochondria and peroxisomes in various cell types such as those in brain, liver, and skin.     

肠道微生物与线粒体之间的互作

肠道微生物与肠道细胞线粒体功能之间的关系十分密切。一方面,肠道微生物可直接或通过短链脂肪酸、硫化氢和一氧化氮等代谢产物间接影响与线粒体相关的能量代谢过程,调节线粒体活性氧的产生,调控线粒体甚至整个机体的免疫反应。另一方面,肠道细胞线粒体功能紊乱和基因组的遗传变异也会影响肠道微生物的组成和功能。本文主要介绍了肠道微生物和线粒体之间的互作关系的最新研究进展,为靶向作用于肠道菌群和线粒体以调节肠道健康提供理论依据。     

Neuron-astrocyte interactions in the regulation of brain energy metabolism: a focus on NMR spectroscopy

An adequate and timely production of ATP by brain cells is of cardinal importance to support the major energetic cost of the rapid processing of information via synaptic and action potentials. Recently, evidence has been accumulated to support the view that the regulation of brain energy metabolism is under the control of an intimate dialogue between astrocytes and neurons. In vitro studies on cultured astrocytes and in vivo studies on rodents have provided evidence that glutamate and Na(+) uptake in astrocytes is a key triggering signal regulating glucose use in the brain. With the advent of NMR spectroscopy, it has been possible to provide experimental evidence to show that energy consumption is mainly devoted to glutamatergic neurotransmission and that glutamate-glutamine cycling is coupled in a approximately 1 : 1 molar stoichiometry to glucose oxidation, at least in the cerebral cortex. This improved understanding of neuron-astrocyte metabolic interactions offers the potential for developing novel therapeutic strategies for many neurological disorders that include a metabolic deficit.     

Living with disabilities in Austria--with a special focus on the capital

Life expectancy, especially in the older age groups, is growing enormously due to better social and medical care. According to published data on disabled people (1997), about 30 % of the total population (7,119,000) in Austria suffer from at least one physical disability. In this study, data from a micro census as well as a report from the Federal Ministry for Social Security and Generations is analyzed to illuminate the situation of impaired people with a focus on the capital Vienna. Among other results, it is anticipated that a large number of disabled people receive no help at all. About every 7th person regularly receives care, every 10th receives daily support. Care intensity increases with age showing a clear progression from the age of 60 onwards. 88% of the main supporting individuals are related to the handicapped person being supported. Women generally exhibit a much higher participation in nursing. The socio-political developments are discussed.     

Metabolic interactions between algal symbionts and invertebrate hosts

Some invertebrates have enlisted autotrophic unicellular algae to provide a competitive metabolic advantage in nutritionally demanding habitats. These symbioses exist primarily but not exclusively in shallow tropical oceanic waters where clear water and low nutrient levels provide maximal advantage to the association. Mostly, the endosymbiotic algae are localized in host cells surrounded by a host-derived membrane (symbiosome). This anatomy has required adaptation of the host biochemistry to allow transport of the normally excreted inorganic nutrients (CO₂, NH₃ and PO₄³⁻) to the alga. In return, the symbiont supplies photosynthetic products to the host to meet its energy demands. Most attention has focused on the metabolism of CO₂ and nitrogen sources. Carbon-concentrating mechanisms are a feature of all algae, but the products exported to the host following photosynthetic CO₂ fixation vary. Identification of the stimulus for release of algal photosynthate in hospite remains elusive. Nitrogen assimilation within the symbiosis is an essential element in the host's control over the alga. Recent studies have concentrated on cnidarians because of the impact of global climate change resulting in coral bleaching. The loss of the algal symbiont and its metabolic contribution to the host has the potential to result in the transition from a coral-dominated to an algal-dominated ecosystem.