[Human mitochondria and mitochondrial genome function as a single dynamic cellular unit].
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Animals↗
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The many shapes of mitochondrial membranes.
The roles of mitochondria in cell death and in aging have generated much excitement in recent years. At the same time, however, a quiet revolution in our thinking about mitochondrial ultrastructure has begun. This revolution started with the use of vital dyes and of green fluorescent protein fusion proteins, showing that mitochondria are very dynamic structures that constantly move, divide and fuse throughout the life of a cell. More recently, some of the first proteins contributing to these various processes have been discovered. Our view of the internal structures of mitochondria has also changed. Three-dimensional reconstructions obtained with high voltage electron microscopy show that cristae are often connected to the mitochondrial inner membrane by thin tubules. These new insights are brought to bear on the wealth of data collected by conventional electron microscopic analysis.
Animals↗
The mitochondrial compartment.
Mitochondria are vital organelles that perform a variety of fundamental functions ranging from the synthesis of ATP through to being intimately involved in programmed cell death. Comprised of at least six compartments: outer membrane, inner boundary membrane, intermembrane space, cristal membranes, intracristal space, and matrix, mitochondria have a complex, dynamic internal structure. This internal dynamism is reflected in the pleomorphy and motility of mitochondria. Mitochondria contain their own DNA (mtDNA), encoding a small number of vital genes, but this role as a genetic vault is not compatible with the role of mitochondria in bioenergetics since electron transport results in the generation of reactive oxygen species (ROS) that induce lesions in the mtDNA. It is hypothesized that ROS shape the morphological organization of the higher plant cell mitochondrial population into a discontinuous whole, and that ROS are a selective pressure affecting the organization of the mitochondrial genome. This review describes how inter- and intra-mitochondrial compartmentalization underpins the biology of this complex organelle.
Aging↗
Mitochondrial dynamics in filamentous fungi.
Mitochondria are essential organelles of eukaryotic cells. They grow continuously throughout the cell cycle and are inherited by daughter cells upon cell division. Inheritance of mitochondria and maintenance of mitochondrial distribution and morphology require active transport of the organelles along the cytoskeleton and depend on membrane fission and fusion events. Many of the molecular components and cellular mechanisms mediating these complex processes have been conserved during evolution across the borders of the fungal and animal kingdoms. During the past few decades, several constituents of the cellular machinery mediating mitochondrial behavior have been identified and functionally characterized. Here, we review the contributions of fungi, with special emphasis on the filamentous fungus Neurospora crassa, to our current understanding of mitochondrial morphogenesis and inheritance.
Actins↗
[Dynamics of Ca2+ transport in rat liver mitochondria in anoxia].
Tetracycline was used as a fluorescent test-antibiotic for Ca2+ ions in rat liver mitochondria. Incubation of the isolated mitochondria under anaerobic conditions at 20 degrees C resulted in a rapid (in 30-min) loss by the mitochondria of the property to accumulate Ca2+. Disturbances of the mitochondrial Ca2+-accumulating property during the survival of the liver developed much more slowly (it took over 2 hours) and were not monotonous; the maximal values were recorded during the 5th-10th and the 60th minutes of survival.
Animals↗
Activity-independent intracellular Ca2+ oscillations are spontaneously generated by ventral spinal neurons during development in vitro.
Within the CNS, distinct neurons may rely on different processes to modulate cytosolic Ca2+ depending on the network developmental phase. In particular, in the immature spinal cord, synchronous electrical discharges are coupled with biochemical signals triggered by intracellular Ca2+ waves. Nevertheless, the presence of neuronal-specific Ca2+ elevations independent from synaptic activity within mammalian spinal networks has not yet been described. The present report is the first description of repetitive calcium events generated by discrete ventral spinal neurons maintained in organotypic culture during in vitro maturation stages crucial for network evolution. Ventral interneurons in one-third of slices displayed spontaneous intracellular calcium transients suppressed by calcium-free extracellular solution or by application of cobalt, and resistant to blockers of network activity like TTX, CNQX, APV, strychnine or bicuculline. Our data suggest a primary role for mitochondria in intracellular calcium oscillations, because CCCP, that selectively collapses the mitochondrial electrochemical gradient, eliminated the ability of these neurons to show activity-independent calcium oscillations. Likewise, CGP-37157, a blocker of mitochondrial Na+/Ca2+ exchanger, inhibited oscillations in the majority of neurons. We propose that spontaneous Ca2+ transients, dynamically regulated by mitochondria, occurred in a discrete cluster of interneurons possibly to guide the development of synaptic connections.
Animals↗
A quantitative analysis of mitochondria during fetal mouse oogenesis.
A quantitative analysis of mitochondrial populations during the meiotic prophase of mouse oogenesis was carried out. The mean absolute area occupied by mitochondria and the mean number of mitochondria per cell increases in a linear fashion from pachytene through dictyate. The mean area occupied by mitochondria increases at pachytene and thereafter. Both small and large aggregations of mitochondria are seen, particularly during the later stages of prophase. Vacuolated mitochondria are present from preleptotene through pachytene. Mitochondria show major dynamic changes throughout fetal mouse oogenesis, which may suggest significant functional activities yet to be elucidated.
Animals↗
Impact of mitochondrial Ca2+ cycling on pattern formation and stability.
Energization of mitochondria significantly alters the pattern of Ca2+ wave activity mediated by activation of the inositol (1,4,5) trisphosphate (IP3) receptor (IP3R) in Xenopus oocytes. The number of pulsatile foci is reduced and spiral Ca2+ waves are no longer observed. Rather, target patterns of Ca2+ release predominate, and when fragmented, fail to form spirals. Ca2+ wave velocity, amplitude, decay time, and periodicity are also increased. We have simulated these experimental findings by supplementing an existing mathematical model with a differential equation for mitochondrial Ca2+ uptake and release. Our calculations show that mitochondrial Ca2+ efflux plays a critical role in pattern formation by prolonging the recovery time of IP3Rs from a refractory state. We also show that under conditions of high energization of mitochondria, the Ca2+ dynamics can become bistable with a second stable stationary state of high resting Ca2+ concentration.
Animals↗
Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology.
Remodeling of mitochondria is a dynamic process coordinated by fusion and fission of the inner and outer membranes of the organelle, mediated by a set of conserved proteins. In metazoans, the molecular mechanism behind mitochondrial morphology has been recruited to govern novel functions, such as development, calcium signaling, and apoptosis, which suggests that novel mechanisms should exist to regulate the conserved membrane fusion/fission machinery. Here we show that phosphorylation and cleavage of the vertebrate-specific Pbeta domain of the mammalian presenilin-associated rhomboid-like (PARL) protease can influence mitochondrial morphology. Phosphorylation of three residues embedded in this domain, Ser-65, Thr-69, and Ser-70, impair a cleavage at position Ser(77)-Ala(78) that is required to initiate PARL-induced mitochondrial fragmentation. Our findings reveal that PARL phosphorylation and cleavage impact mitochondrial dynamics, providing a blueprint to study the molecular evolution of mitochondrial morphology.
Amino Acid Sequence↗
Subcellular heterogeneity of mitochondrial function and dysfunction: evidence obtained by confocal imaging.
Beyond their fundamental role in energy metabolism, mitochondria perform a great variety of other important functions (e.g. in Ca2+ homeostasis, apoptosis, thermogenesis, etc.), thus suggesting their region-specific specializations and intracellular heterogeneity. Although mitochondrial functional heterogeneity has been demonstrated for several cell types, its origin and role under physiological and, in particular, pathophysiological conditions, where the extent of heterogeneity may significantly increase, remain to be elucidated. The present work thus investigated the static and dynamic heterogeneity of mitochondria and mitochondrial function in various cell types in which mitochondria may cope with specific functions including cardiomyocytes, hepatocytes and some cultured carcinoma cells. Modern confocal and two-photon fluorescent microscopy was used for the investigation and direct imaging of region-specific mitochondrial function and heterogeneity. Analysis of the autofluorescence of mitochondrial flavoproteins in hepatocytes and carcinoma cells permitted significant intracellular heterogeneity of mitochondrial redox state to be demonstrated. Comparative homogeneity and clear colocalization of mitochondrial flavoproteins, membrane potential and calcium-sensitive probes were observed in both isolated cardiomyocytes and permeabilized myocardial fibers. After ischemia reperfusion, however, or under conditions of substrate deprivation, significant heterogeneity of all these parameters was detected. Some methodological issues, mechanistic aspects, possible metabolic consequences of mitochondrial functional heterogeneity and its impact under pathological conditions are discussed.
Animals↗
[Organization and dynamics of the mitochondrial compartment].
Mitochondria are essential organelles that are involved in numerous metabolic pathways and produce the major part of intracellular ATP by oxidative phosphorylation. Their ultrastructure was solved in the 1950s by electron microscopic analysis of ultrathin sections. Based on these pioneering studies and on the endosymbiotic origin of mitochondria, cells are often assumed to contain numerous independent mitochondria with a size similar to that of bacteria. However, electron microscopy of thick sections reveals that mitochondria form elongated and branched filaments. Optical microscopy of living cells demonstrates that mitochondrial filaments continuously modify their position and morphology and that they undergo frequent fission and fusion reactions. In this review, we revise the actual knowledge on the ultrastructure, the organization and the dynamics of the mitochondrial compartment. We review recent findings showing that mitochondria exchange molecules by fusion and we present the main proteins involved in mitochondrial fusion and fission reactions. Finally, we discuss the functional and physiological relevance of mitochondrial dynamics.
Animals↗
[Mechanisms of adaptation to cold in man and animals].
The paper presents the results of studies of metabolic processes in the Arctic and Antarctic winters, members of Polar expeditions, and inhabitants of the Far North. There is a relationship between the metabolism and the length of residence in the area of low temperatures, lifestyle, and occupation. The experiments have shown changes in the phosphorylizing activity of rat hepatic mitochondria in the dynamics of cold adaptation in animals. In addition to the hormonal status and antioxidative system, serum lipoproteins were found to determine the response of the body to cold exposure. The regulatory role of the lipoprotein components apoproteins is discussed in the paper.
Adaptation, Physiological↗
Deletion of mdmB impairs mitochondrial distribution and morphology in Aspergillus nidulans.
Mitochondria form a dynamic network of interconnected tubes in the cells of Saccharomyces cerevisiae or filamentous fungi such as Aspergillus nidulans, Neurospora crassa, or Podospora anserina. The dynamics depends on the separation of mitochondrial fragments, their movement throughout the cell, and their subsequent fusion with the other parts of the organelle. Interestingly, the microtubule network is required for the distribution in N. crassa and S. pombe, while S. cerevisiae and A. nidulans appear to use the actin cytoskeleton. We studied a homologue of S. cerevisiae Mdm10 in A. nidulans, and named it MdmB. The open reading frame is disrupted by two introns, one of which is conserved in mdm10 of P. anserina. The MdmB protein consists of 428 amino acids with a predicted molecular mass of 46.5 kDa. MdmB shares 26% identical amino acids to Mdm10 from S. cerevisiae, 35% to N. crassa, and 32% to the P. anserina homologue. A MdmB-GFP fusion protein co-localized evenly distributed along mitochondria. Extraction of the protein was only possible after treatment with a non-ionic and an ionic detergent (1% Triton X-100; 0.5% SDS) suggesting that MdmB was tightly bound to the mitochondrial membrane fraction. Deletion of the gene in A. nidulans affected mitochondrial morphology and distribution at 20 degrees C but not at 37 degrees C. mdmB deletion cells contained two populations of mitochondria at lower temperature, the normal tubular network plus some giant, non-motile mitochondria.
Amino Acid Sequence↗
Functional diffusive/convective interaction determining maximal oxygen uptake in humans: its modeling perspective.
In this short review, the frame of current understandings concerning what determines the upper limit of oxygen flow from the ambient air to the muscular mitochondria during maximal dynamic exercise in humans (i.e., VO2max), was summarized mainly from its modeling perspective. Several models and experimental evidences which appeared repeatedly in the recent debates regarding the factors limiting VO2max, were adopted and criticized. In conclusion, VO2max is determined in particular by the integrated interaction between the diffusive and convective factors both to lung O2-loading and muscular O2-unloading in the pathway for O2 flow, although all experimental observations cannot be satisfactorily explained at the present time.
Exercise↗
Get the balance right: mitofusins roles in health and disease.
Mitochondria are highly dynamic organelles exhibiting an elaborate morphology and fine structure. Fusion and fission processes contribute to the maintenance and dynamics of mitochondrial morphology. The Mitofusins, a class of evolutionary conserved GTPases of the mitochondrial outer membrane, are essential for the controlled fusion of mitochondrial membranes. Genetic and biochemical data propose a model in which functional domains, such as the GTPase domain and the C-terminally located coiled coil structure, act in an orchestrated manner to coordinate the tethering and mitochondrial outer membrane fusion. In addition, recent reports shed new light on the physiological importance of Mitofusin function suggesting a role in mitochondrial metabolism, apoptosis as well as cellular signalling. Mutations identified in the human Mfn2 gene from patients with the peripheral neuropathy Charcot-Marie-Tooth Type 2A invoke a direct correlation between mitochondrial morphology and function.
Adaptor Proteins, Signal Transducing↗
Multiple conformations of physiological membrane-bound cytochrome c.
One-tenth of cytochrome c (cyt c) remains bound to the inner mitochondrial membrane (IMM) at physiological ionic strength (I; i.e. , I approximately 150 mM), exhibiting decreased electron transport (ET) activity. We now show that this form of membrane-bound cyt c (MB-cyt c) can be obtained in vitro and that binding to membranes at low I generates an additional conformation with higher ET activity. This low I bound form of MB-cyt c (MBL-cyt c) exhibited intrinsic ET rates similar to those of electrostatically bound cyt c (EB-cyt c). The ET activity of IMM-bound MB-cyt c approached slowly that of MBL-cyt c or EB-cyt c, suggesting that MB-cyt c converts to MBL-cyt c while bound to IMM. When maintained at physiological I, both forms of MB-cyt c were released from the membrane, indicating that they convert to an EB-cyt c-like form. This process may be very dynamic in cellular mitochondria, as binding and release for both MB-cyt c forms increased considerably with temperature. I-Dependent binding of MB-cyt c does not require IMM, and it can be reproduced using large or small unilamellar vesicles (SUV). Using SUV-cyt c complexes, we characterized the secondary structure of MB-cyt c and MBL-cyt c by circular dichroism. Conformational analysis revealed that cyt c binding as MB-cyt c decreases its alpha-helical content (70-79%) and increases its beta-sheet up to 135%. The secondary structure of MBL-cyt c was similar to that of EB-cyt c and soluble cyt c, with a modest increase in beta-sheet. Taken together, our experiments suggest that physiological cyt c exists in soluble and membrane-bound conformations with similar ET activity, which may exchange very rapidly, and that soluble hydrophilic proteins can bind transiently to biomembranes.
Animals↗
The mitochondrial genome in embryo technologies.
The mammalian mitochondrial genome encodes for 37 genes which are involved in a broad range of cellular functions. The mitochondrial DNA (mtDNA) molecule is commonly assumed to be inherited through oocyte cytoplasm in a clonal manner, and apparently species-specific mechanisms have evolved to eliminate the contribution of sperm mitochondria after natural fertilization. However, recent evidence for paternal mtDNA inheritance in embryos and offspring questions the general validity of this model, particularly in the context of assisted reproduction and embryo biotechnology. In addition to normal mt DNA haplotype variation, oocytes and spermatozoa show remarkable differences in mtDNA content and may be affected by inherited or acquired mtDNA aberrations. All these parameters have been correlated with gamete quality and reproductive success rates. Nuclear transfer (NT) technology provides experimental models for studying interactions between nuclear and mitochondrial genomes. Recent studies demonstrated (i) a significant effect of mtDNA haplotype or other maternal cytoplasmic factors on the efficiency of NT; (ii) phenotypic differences between transmitochondrial clones pointing to functionally relevant nuclear-cytoplasmic interactions; and (iii) neutral or non-neutral selection of mtDNA haplotypes in heteroplasmic conditions. Mitochondria form a dynamic reticulum, enabling complementation of mitochondrial components and possibly mixing of different mtDNA populations in heteroplasmic individuals. Future directions of research on mtDNA in the context of reproductive biotechnology range from the elimination of adverse effects of artificial heteroplasmy, e.g. created by ooplasm transfer, to engineering of optimized constellations of nuclear and cytoplasmic genes for the production of superior livestock.
Animals↗
[MITOCHONDRIAL DIVISIONS AND ABNORMALITIES IN THE RAT LIVER SUBJECTED TO ISCHEMIA].
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Ischemia↗