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PubMed1991

Protective effects of idebenone against alterations in dynamic microstructure induced by lipid peroxidation in rat cardiac mitochondria.

The antioxidative effect of idebenone was studied in isolated mitochondria from the rat heart. Variables for dynamic microstructure, membrane viscosity and wobbling angle of phospholipids, were measured by means of a nanosecond time-resolved fluorometer. Exposure of isolated cardiac mitochondria to oxidative conditions in vitro caused significant alterations in lipid peroxidation, wobbling angle of phospholipids and membrane viscosity. Exposure of mitochondria to oxidative conditions after idebenone pretreatment resulted in no significant alterations in membrane viscosity and wobbling angle of phospholipids. Alterations in these variables seemed to be related to the amount of peroxidized lipid. Protection of phospholipids against peroxidation by antioxidative substances is effective in maintaining nearly normal physical properties in the dynamic microstructure of cardiac mitochondrial membranes.

Animals↗
PubMed2005

Emerging functions of mammalian mitochondrial fusion and fission.

Mitochondria provide a myriad of services to the cell, including energy production, calcium buffering and regulation of apoptosis. How these diverse functions are coordinated among the hundreds of mitochondria in a given cell is largely unknown, but is probably dependent on the dynamic nature of mitochondria. In this review, we explore the latest developments in mitochondrial dynamics in mammals. These studies indicate that mitofusins and OPA1 are essential for mitochondrial fusion, whereas Fis1 and Drp1 are essential for mitochondrial fission. The overall morphology of the mitochondrial population depends on the relative activities of these two sets of proteins. In addition to the regulation of mitochondrial shape, these molecules also play important roles in cell and tissue physiology. Perturbation of mitochondrial fusion results in defects in mitochondrial membrane potential and respiration, poor cell growth and increased susceptibility to cell death. These cellular observations may explain why mitochondrial fusion is essential for embryonic development. Two inherited neuropathies, Charcot-Marie-Tooth type 2A and autosomal dominant optic atrophy, are caused by mutations in mitofusin 2 and OPA1, suggesting that proper regulation of mitochondrial dynamics is particularly vital to neurons. Mitochondrial fission accompanies several types of apoptotic cell death and appears important for progression of the apoptotic pathway. These studies provide insight into how mitochondria communicate with one another to coordinate mitochondrial function and morphology.

Animals↗
PubMed2006

Orchestration of lymphocyte chemotaxis by mitochondrial dynamics.

Lymphocyte traffic is required to maintain homeostasis and perform appropriate immunological reactions. To migrate into inflamed tissues, lymphocytes must acquire spatial and functional asymmetries. Mitochondria are highly dynamic organelles that distribute in the cytoplasm to meet specific cellular needs, but whether this is essential to lymphocyte functions is unknown. We show that mitochondria specifically concentrate at the uropod during lymphocyte migration by a process involving rearrangements of their shape. Mitochondrial fission facilitates relocation of the organelles and promotes lymphocyte chemotaxis, whereas mitochondrial fusion inhibits both processes. Our data substantiate a new role for mitochondrial dynamics and suggest that mitochondria redistribution is required to regulate the motor of migrating cells.

Adenosine Triphosphate↗
PubMed2006

Systematic characterization of nuclear proteome during apoptosis: a quantitative proteomic study by differential extraction and stable isotope labeling.

Identification and characterization of the nuclear proteome is important for detailed understanding of multiple signaling events in eukaryotic cells. Toward this goal, we extensively characterized the nuclear proteome of human T leukemia cells by sequential extraction of nuclear proteins with different physicochemical properties using three buffer conditions. This large scale proteomic study also tested the feasibility and technical challenges associated with stable isotope labeling by amino acids in cell culture (SILAC) to uncover quantitative changes during apoptosis. Analyzing proteins from three nuclear fractions extracted from naive and apoptotic cells generated 780,530 MS/MS spectra that were used for database searching using the SEQUEST algorithm. This analysis resulted in the identification and quantification of 1,174 putative nuclear proteins. A number of known nuclear proteins involved in apoptosis as well as novel proteins not known to be part of the nuclear apoptotic machinery were identified and quantified. Consistent with SILAC-based quantifications, immunofluorescence staining of nucleus, mitochondria, and some associated proteins from both organelles revealed a dynamic recruitment of mitochondria into nuclear invaginations during apoptosis.

Amino Acid Sequence↗
PubMed2003

Parasite mitochondria as drug target: diversity and dynamic changes during the life cycle.

Parasites have developed a wide variety of physiological functions to survive within the specialized environments of the host. Regarding energy metabolism, which represents an essential factor for survival, parasites adapt low oxygen tension in host mammals using metabolic systems that differ substantially from those of the host. Most parasites do not use free oxygen available within the host, but employ systems other than oxidative phosphorylation for ATP synthesis. Furthermore, parasites display marked changes in mitochondrial morphology and components during the life cycle, and these represent very interesting elements of biological processes such as developmental control and environmental adaptation. The enzymes in parasite-specific pathways offer potential targets for chemotherapy. Cyanide-insensitive trypanosome alternative oxidase (TAO) is the terminal oxidase of the respiratory chain of long slender bloodstream forms of the African trypanosome, which causes sleeping sickness. Recently, the most potent inhibitor of TAO to date, ascofuranone, was isolated from the phytopathogenic fungus, Ascochyta visiae. The inhibitory mechanisms of ascofuranone have been revealed using recombinant enzyme. Parasite-specific respiratory systems are also found in helminths. The NADH-fumarate reductase system in mitochondria form a final step in the phosphoenolpyruvate carboxykinase (PEPCK)-succinate pathway, which plays an important role in anaerobic energy metabolism for the Ascaris suum adult. Enzymes in this system, such as NADH-rhodoquinone reductase (complex I) and rhodoquinol-fumarate reductase (complex II), form promising targets for chemotherapy. In fact, a specific inhibitor of nematode complex I, nafuredin, has been found in mass-screening using parasite mitochondria.

Amino Acid Sequence↗
PubMed1996

Type I brain hexokinase: axonal transport and membrane associations within central nervous system presynaptic terminals.

While studying the delivery of cytoplasmic proteins to the presynaptic terminals of CNS neurons, we discovered unique characteristics of one protein (p118) conveyed in slow component b (SCb) of axonal transport, the large group of proteins representing the cytoplasmic matrix. Alone among the SCb group, p118 coisolated with the synaptic junctional complex on biochemical fractionation of the radiolabeled synaptic regions. Purification and amino acid sequencing of this protein revealed it is most likely the guinea pig form of type I (brain) hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1). Further biochemical treatments were consistent with this identity. The majority of type I brain hexokinase has been thought to be associated primarily with membranes, in particular the mitochondrial outer membrane. We found that the majority of type I hexokinase is transported toward the terminals at a rate at least 10 times slower than that exhibited by the maximal or average rate of mitochondria. This suggests that, in the axon, the enzyme exhibits transient or dynamic interactions with mitochondria that are moving more rapidly. It is not clear whether hexokinase binds exclusively to mitochondria, or also exhibits association with nonmitochondrial membranes. The unexpected enrichment of hexokinase during synaptic junctional complex purification may result from its strong association with the presynaptic membrane portion of the synapse.

Amino Acid Sequence↗
PubMed2006

Dynamics of reductive genome evolution in mitochondria and obligate intracellular microbes.

Reductive evolution in mitochondria and obligate intracellular microbes has led to a significant reduction in their genome size and guanine plus cytosine content (GC). We show that genome shrinkage during reductive evolution in prokaryotes follows an exponential decay pattern and provide a method to predict the extent of this decay on an evolutionary timescale. We validated predictions by comparison with estimated extents of genome reduction known to have occurred in mitochondria and Buchnera aphidicola, through comparative genomics and by drawing on available fossil evidences. The model shows how the mitochondrial ancestor would have quickly shed most of its genome, shortly after its incorporation into the protoeukaryotic cell and prior to codivergence subsequent to the split of eukaryotic lineages. It also predicts that the primary rickettsial parasitic event would have occurred between 180 and 425 million years ago (MYA), an event of relatively recent evolutionary origin considering the fact that Rickettsia and mitochondria evolved from a common alphaproteobacterial ancestor. This suggests that the symbiotic events of Rickettsia and mitochondria originated at different time points. Moreover, our model results predict that the ancestor of Wigglesworthia glossinidia brevipalpis, dated around the time of origin of its symbiotic association with the tsetse fly (50-100 MYA), was likely to have been an endosymbiont itself, thus supporting an earlier proposition that Wigglesworthia, which is currently a maternally inherited primary endosymbiont, evolved from a secondary endosymbiont.

Base Composition↗
PubMed2005

[Mitochondria and their role in cell metabolism].

Mitochondria are subcellular organelles of the endosymbiotic origin. They are bounded by double membrane and contain their own DNA. Recent advance in 3D microscopy have contributed a better understanding of mitochondrial structure. Mitochondria are highly dynamic organelles with a very complex structure of the inner membrane. In cells, mitochondria create an interconnected reticulum. Beyond a fundamental role in energy production, they also play key roles in thermogenesis, maintenance of cellular redox potential, Ca2+ homeostasis, ROS production, cell signaling and cell death. Disturbances in mitochondrial metabolism are known to play a role not only in rare genetics disorders, but have also been implicated in many common diseases of aging. Conventional studies of mitochondrial metabolism are based on the isolation of intact organelles. Because of mitochondrial complex roles rises a need to assay mitochondrial functions in situ. The activity of respiration and oxidative phosphorylation in intact and permeabilized cells can be measured by using high resolution respirometry. We can estimate various mitochondrial functions in living cells by using fluorescent cation dyes.

Animals↗
PubMed2004

Dynamics of protein nitration in cells and mitochondria.

Nitric oxide is a precursor of reactive nitrating species such as peroxynitrite and nitrogen dioxide that modify proteins to generate 3-nitrotyrosine. Many diseases are associated with increased levels of protein-bound nitrotyrosine, and this is used as a marker for oxidative damage. However, the regulation of protein nitration and its role in cell function are unclear. We demonstrate that biological protein nitration can be a specific and dynamic process. Proteins were nitrated in distinct temporal patterns in cells undergoing inflammatory activation, and protein denitration and renitration occurred rapidly in respiring mitochondria. The targets of protein nitration varied over time, which may reflect their sensitivity to nitration, expression pattern, or turnover. The dynamic nature of the nitration process was revealed by denitration and renitration of proteins occurring within minutes in mitochondria that were subject to hypoxiaanoxia and reoxygenation. Our results have implications that are particularly important for ischemia-reperfusion injury.

Cell Hypoxia↗
PubMed1993

Motional dynamics of functional cytochrome c delivered by low pH fusion into the intermembrane space of intact mitochondria.

We have investigated the motional dynamics of cytochrome c in the intact, functional rat liver mitochondrion. To do this, functional, FITC-cytochrome c (fluorescein isothiocyanate monoderivatized cytochrome c) was incorporated into the intermembrane space (IMS) of intact mitochondria through encapsulation of cytochrome c into asolectin liposomes followed by low pH-induced fusion of the liposomes with the outer membranes of the mitochondria. A cytochrome c controlled enrichment of between 15%-50% (1800-7200 molecules incorporated per mitochondrion) was obtained. All cytochrome c incorporated, regardless of the quantity, participated in the function of electron transport, indicative of a functional, independent random diffusant. Resonance energy transfer was determined from the IMS-entrapped functional FITC-cytochrome c to octadecylrhodamine B incorporated into the mitochondrial membranes. Resonance energy transfer from FITC-cytochrome c to octadecylrhodamine B in isolated inner or outer mitochondrial membranes (IMM and OMM, respectively) was also measured. We found substantial differences in the effects of ionic strength (I) on the proximity of cytochrome c to isolated IMM and OMM. Interactions with isolated IMM were very dynamic, i.e., very I-dependent, and cytochrome c binding to IMM was significant only at very low I. I-dependent interactions of cytochrome c with isolated OMM were less I-dependent than those for the IMM. However, FITC-cytochrome c was essentially released from IMM and OMM at physiological I. The proximity of FITC-cytochrome c to each mitochondrial membrane after its incorporation into the IMS of intact mitochondria in the condensed configuration was estimated at different external, bulk I using: (a) resonance energy transfer from IMS-entrapped FITC-cytochrome c to octadecylrhodamine B-label evenly distributed in both mitochondrial membranes; and (b) resonance energy transfer from IMS-entrapped FITC-cytochrome c to octadecylrhodamine B-label concentrated in the OMM. Resonance energy transfer showed that the average distance between cytochrome c and the two IMS-membrane surfaces increased with increasing IMS-I, approaching a maximal measurable distance of 85 A at 150 mM I. This result is consistent with a dissociation of FITC-cytochrome c and both membranes of intact mitochondria at physiological I, i.e., when the activity of cytochrome c in electron transport is highest. Our findings reveal a primarily three-dimensional diffusion mode for IMS-cytochrome c during its function in electron transport in intact mitochondria at physiological I, and offer further evidence that mitochondrial electron transport is a process driven by random collisions between its independently diffusing electron transferring, redox components.

Animals↗
PubMed1994

Human mitochondria and mitochondrial genome function as a single dynamic cellular unit.

rho 0 HeLa cells entirely lacking mitochondrial DNA (mtDNA) and mitochondrial transfection techniques were used to examine intermitochondrial interactions between mitochondria with and without mtDNA, and also between those with wild-type (wt) and mutant-type mtDNA in living human cells. First, unambiguous evidence was obtained that the DNA-binding dyes ethidium bromide (EtBr) and 4',6-diamidino-2-phenylindole (DAPI) exclusively stained mitochondria containing mtDNA in living human cells. Then, using EtBr or DAPI fluorescence as a probe, mtDNA was shown to spread rapidly to all rho 0 HeLa mitochondria when EtBr- or DAPI-stained HeLa mitochondria were introduced into rho 0 HeLa cells. Moreover, coexisting wt-mtDNA and mutant mtDNA with a large deletion (delta-mtDNA) were shown to mix homogeneously throughout mitochondria, not to remain segregated by use of electron microscopic analysis of cytochrome c oxidase activities of individual mitochondria as a probe to identify mitochondria with predominantly wt- or delta-mtDNA in single cells. This rapid diffusion of mtDNA and the resultant homogeneous distribution of the heteroplasmic wt- and delta-mtDNA molecules throughout mitochondria in a cell suggest that the mitochondria in living human cells have lost their individuality. Thus, the actual number of mitochondria per cell is not of crucial importance, and mitochondria in a cell should be considered as a virtually single dynamic unit.

DNA, Mitochondrial↗
PubMed2006

Estrogen exerts a spatial and temporal influence on reactive oxygen species generation that precedes calcium uptake in high-capacity mitochondria: implications for rapid nongenomic signaling of cell growth.

Novel findings that emerged from this study underscore the fact that the dynamic nature of mitochondria leads to functional heterogeneity of [Ca(2+)](mito) with respect to estrogen actions in MCF7 cells. We show that estrogen exposure to cells increased [Ca(2+)](mito) in a high-calcium capacity mitochondrial population but not in low-calcium capacity mitochondria. Physiological concentrations of 17beta-estradiol (E2) modulated Ca(2+)(mito) uptake within 90 s. Interestingly, this calcium response lagged behind the induction of mitochondrial reactive oxygen species (mtROS). The rapid induction of Ca(2+)(mito) in response to E2 and its inhibition by mitochondrial blockers suggest that mitochondria are early nongenomic targets of E2. This suggests that a subpopulation of mitochondria is recruited to respond to new metabolic requirements required by estrogen triggers or, as in this case, E2-induced Ca(2+)(mito) and/or mtROS promotes oxidative signaling without involving nuclear estrogen receptor signaling. Although the early E2-induced Ca(2+) did not alter the expression of genes involved in calcium signaling pathways, an intracellular calcium chelator BAPTA-AM and the Ca(2+)(mito) uniporter blocker ruthenium red prevented E2-induced cell growth. We have shown recently that E2-mediated ROS production controls the promoter activity of cyclin D1 by post-translational modification of calcium sensitive transcription factor CREB. The findings of this study offer a new paradigm that rapid E2-induced changes in mtROS and Ca(2+)(mito) are involved in cell cycle progression presumably through the control of early cell cycle genes. Targeting mitochondria to disrupt communication between mitochondria and ROS/Ca(2+) signaling pathways may provide the basis for a novel anticancer strategy for the treatment of estrogen-dependent breast cancer.

Breast Neoplasms↗
PubMed2000

Yeast mitochondrial dynamics: fusion, division, segregation, and shape.

Mitochondria are essential organelles found in virtually all eukaryotic cells that play key roles in a variety of cellular processes. Mitochondria show a striking heterogeneity in their number, location, and shape in many different cell types. Although the dynamic nature of mitochondria has been known for decades, the molecules and mechanisms that mediate these processes are largely unknown. Recently, several laboratories have isolated and analyzed mutants in the yeast Saccharomyces cerevisiae defective in mitochondrial fusion and division, in the segregation of mitochondria to daughter cells, and in the establishment and maintenance of mitochondrial shape. These studies have identified several proteins that appear to mediate different aspects of mitochondrial morphogenesis. Although it is clear that many additional components have yet to be identified, some of the newly discovered proteins raise intriguing possibilities for how the processes of mitochondrial division, fusion, and segregation occur. Below we summarize our current understanding of the molecules known to be required for yeast mitochondrial dynamics.

Cell Division↗
PubMed2000

Recent structural insight into mitochondria gained by microscopy.

Novel applications of microscopy have recently provided new insights into mitochondrial structures. Diverse techniques such as high resolution scanning electron microscopy, transmission electron microscopy, electron microscope tomography and light microscopy have contributed a better understanding of mitochondrial compartmentalization, dynamic networks of mitochondria, intermembrane bridges, segregation of mitochondrial DNA and contacts with the endoplasmic reticulum among other aspects. This review focuses on advances reported in the last five years concerning aspects of mitochondrial substructure or dynamics gained through new techniques, whether they be novel microscope methods or new ways to prepare or label specimens. Sometimes these advances have produced surprising results and more often than not, they have challenged current conceptions of how mitochondria work.

Animals↗
PubMed2006

Chondrocyte deformation induces mitochondrial distortion and heterogeneous intracellular strain fields.

Chondrocyte mechanotransduction is poorly understood but may involve cell deformation and associated distortion of intracellular structures and organelles. This study quantifies the intracellular displacement and strain fields associated with chondrocyte deformation and in particular the distortion of the mitochondria network, which may have a role in mechanotransduction. Isolated articular chondrocytes were compressed in agarose constructs and simultaneously visualised using confocal microscopy. An optimised digital image correlation technique was developed to calculate the local intracellular displacement and strain fields using confocal images of fluorescently labelled mitochondria. The mitochondria formed a dynamic fibrous network or reticulum, which co-localised with microtubules and vimentin intermediate filaments. Cell deformation induced distortion of the mitochondria, which collapsed in the axis of compression with a resulting loss of volume. Compression generated heterogeneous intracellular strain fields indicating mechanical heterogeneity within the cytoplasm. The study provides evidence supporting the potential involvement of mitochondrial deformation in chondrocyte mechanotransduction, possibly involving strain-mediated release of reactive oxygen species. Furthermore the heterogeneous strain fields, which appear to be influenced by intracellular structure and organisation, may generate significant heterogeneity in mechanotransduction behaviour for cells subjected to identical levels of deformation.

Animals↗
PubMed2006

High resolution imaging of live mitochondria.

Classically, mitochondria have been studied by biochemical, genetic and electron microscopic approaches. In the last two decades, it became evident that mitochondria are highly dynamic organelles that are frequently dividing and fusing, changing size and shape and traveling long distances throughout the life of a cell. The study of the complex structural changes of mitochondria in vivo became possible with the advent of fluorescent labeling techniques in combination with live cell imaging microscopy. This review aims to provide an overview on novel fluorescent markers that are used in combination with mitochondrial fusion assays and various live cell microscopy techniques to study mitochondrial dynamics. In particular, approaches to study the movement of mitochondrial proteins and novel imaging techniques (FRET imaging-, 4Pi- and STED-microscopy) that provide high spatial resolution are considered.

Animals↗
PubMed2003

Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA.

The structure of mitochondria is highly dynamic and depends on the balance of fusion and fission processes. Deletion of the mitochondrial dynamin-like protein Mgm1 in yeast leads to extensive fragmentation of mitochondria and loss of mitochondrial DNA. Mgm1 and its human ortholog OPA1, associated with optic atrophy type I in humans, were proposed to be involved in fission or fusion of mitochondria or, alternatively, in remodeling of the mitochondrial inner membrane and cristae formation (Wong, E. D., Wagner, J. A., Gorsich, S. W., McCaffery, J. M., Shaw, J. M., and Nunnari, J. (2000) J. Cell Biol. 151, 341-352; Wong, E. D., Wagner, J. A., Scott, S. V., Okreglak, V., Holewinske, T. J., Cassidy-Stone, A., and Nunnari, J. (2003) J. Cell Biol. 160, 303-311; Sesaki, H., Southard, S. M., Yaffe, M. P., and Jensen, R. E. (2003) Mol. Biol. Cell, in press). Mgm1 and its orthologs exist in two forms of different lengths. To obtain new insights into their biogenesis and function, we have characterized these isoforms. The large isoform (l-Mgm1) contains an N-terminal putative transmembrane segment that is absent in the short isoform (s-Mgm1). The large isoform is an integral inner membrane protein facing the intermembrane space. Furthermore, the conversion of l-Mgm1 into s-Mgm1 was found to be dependent on Pcp1 (Mdm37/YGR101w) a recently identified component essential for wild type mitochondrial morphology. Pcp1 is a homolog of Rhomboid, a serine protease known to be involved in intercellular signaling in Drosophila melanogaster, suggesting a function of Pcp1 in the proteolytic maturation process of Mgm1. Expression of s-Mgm1 can partially complement the Deltapcp1 phenotype. Expression of both isoforms but not of either isoform alone was able to partially complement the Deltamgm1 phenotype. Therefore, processing of l-Mgm1 by Pcp1 and the presence of both isoforms of Mgm1 appear crucial for wild type mitochondrial morphology and maintenance of mitochondrial DNA.

Blotting, Western↗
PubMed2001

Quantitative and ultrastructural analysis of the chondriome in ovogenesis and embryogenesis of the sea urchin Paracentrotus lividus. 2. Growth and proliferation of mitochondria in embryogenesis.

The dynamics of structural changes of the chondriome in the early development of the sea urchin Paracentrotus lividus was studied. Mature eggs and embryos at various stages of cleavage were used for quantitative and ultrastructural analysis based on computerized 3D reconstruction from serial ultrathin sections. The following structural transformations of the chondriome were shown to occur in the course of embryogenesis: (i) 15 min after fertilization, mitochondrial clusters disintegrate, and mitochondrial division is induced. At the stage of two blastomeres the population of mitochondria increases twofold; (ii) the mitochondria divide by means of the contraction of both outer and inner membranes. The forming furrow divides the "parental" mitochondrion into two equal "daughter" parts; (iii) at the four-cell stage the division ceases, and mitochondria start to grow, so that the mitochondrial length increases; (iv) cell differentiation further stimulates elongation of rod-shaped mitochondria, and the ratio of rod-shaped to spherical mitochondria changes; (v) in an unfertilised egg, the mitochondria are in a condensed form; after fertilisation all the mitochondria acquire a conventional form. Modern concepts of chondriome proliferation in eukaryotic cells are discussed.

Animals↗