[DYNAMICS OF CHANGES IN THE STRUCTURE AND MASS OF MITOCHONDRIA OF THE HEART DURING THE PROCESS OF ITS HYPERFUNCTION AND HYPERTROPHY].
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Animals↗
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[The seasonal dynamics of the adenine nucleotide level in the liver mitochondria of the frog Rana temporaria].
ATP, ADP and AMP content of liver mitochondria has been determined in frogs immediately after isolation during autumn, winter and spring periods. Seasonal changes in adenine nucleotides in frogs are similar to those observed in rat liver mitochondria during early postnatal ontogenesis. It is suggested that in frogs seasonal changes in liver intramitochondrial adenine nucleotides depend on the hormonal condition of animals.
Adenine Nucleotides↗
[Dynamics of the ribonucleoprotein level of the tigroid and mitochondria in the cat's spinal motor neurons during their stimulation and inhibition].
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Animals↗
[Dynamics of the ribonucleoprotein level of the tigroid and mitochondria in the cat's spinal motor neurons during their stimulation and inhibition].
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Animals↗
[Intermembrane electron transport in the dynamics of high-amplitude swelling of rat liver mitochondria].
The rate of rotenone insensitive NADH oxidation depending on the extent of rat liver mitochondria swelling in isotonic sucrose medium has been studied. The rate of exogenous NADH oxidation was determined fluorimetrically in the presence of 4 microM cytochrome c in the medium after the inhibition of high-amplitude swelling at its different stages by means of rotenone +Mg2+ + trifluoromethoxyphenylhydrasonecarbonylcyanide (FCCP) addition. Activation of external pathway of NADH oxidation in phosphate containing medium was conditioned by quick energy and phosphate-dependent mitochondria swelling that leads to the outer membrane disruption. An increase in the rate of NADH oxidation as a result of the outer membrane disruption during high amplitude swelling in isotonic sucrose medium has been shown to be nearly proportional to the extent of the decrease in optical density of mitochondria suspension. Similar decrease in optical density of homogenates incubated 25-30 min in isotonic sucrose medium was also accompanied by a significant increase in Mg(2+)-cytochrome c-dependent rotenone insensitive NADH oxidation. A decrease in optical density of liver homogenates was prevented by EGTA+2+, rotenone+Mg2++FCCP, rotenone or FCCP alone and was nearly completely inhibited at any stages of changes by means of rotenone+Mg2++FCCP addition that usually inhibit mitochondrial swelling. That means that the rate of Mg(2+)-cytochrome-c-dependent rotenone insensitive NADH oxidation in homogenates may be used as the simple method to evaluate the outer mitochondrial membrane disruption with the purpose to analyse the liver bioptate to study the effect of hormonal, xenobiotic and physical factors on mitochondrial macrostructure.
Animals↗
Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.
Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1-/- cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1-/- cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.
Humans↗
[Change in the hexokinase activity of the rat myocardial and skeletal muscle mitochondria and cytoplasm in fasting and on a carbohydrate diet].
Dynamics of the hexokinase activity was stuided in mitochondria and cytoplasm of skeletal muscle and myocardium in rats which were subjected to fasting for three days and then were given a carbohydrate diet. It is established that the hexokinase activity in mitochondria (especially in the miocardium) lowers during fasting to a less extent as compared to cytoplasm and is not restored when feeding on carbohydrates, evidently, due to different quantitative ratio of isoenzymes. It is shown that hexokinase from the myocardium solubilizes more easily that from the skeletal muscles.
Animals↗
[Dynamic interaction between plasma membrane structures and intracellular calcium stores in neurons of the spinal cord ganglia].
We studied the dynamic contribution of endoplasmic reticulum and mitochondria to depolarization-induced Ca2+ transients in small (18-24 microm) DRG neurons of rats. We have used the application of 10 microM of mitochondrial protonophore CCCP for switching off the calcium uptake by mitochondrial uniporter. For depletion of the store of endoplasmic reticulum we applied 1 microM of thapsigargin. Depolarization-induced transients in control conditions and in conditions when one of the mechanisms (mitochondria or endoplasmic reticulum) does not participate in the forming of the shape of Ca2+ transient have been studied. This allowed us to clarify the kinetics of mitochondrial and endoplasmic reticulum uptake and release of calcium in the process of the neuronal activity. We have determined the main characteristics of functioning of above-named calcium stores in the process of cell excitation, such as time of the beginning of uptake, time and duration of maximum activity etc. We concluded, that mitochondria and endoplasmic reticulum are acting in opposite directions at least in the phase of the beginning of the transient. Mitochondria are limiting the amplitude of the transient during depolarization, at the same time the endoplasmic reticulum is increasing the amplitude of the transient by CICR (calcium-induced calcium release) mechanism. Mitochondria store calcium released from endoplasmic reticulum by application of 30 mM caffeine. Inhibition of the mitochondrial uniporter results in reduction of amplitude of repetitive caffeine application compared with control conditions. We have compared the kinetics of mitochondrial participation in the formation of calcium signal when the initial sources of calcium ions were different. Our results allow us to suggest a close functional dynamic interactions between mitochondria and endoplasmic reticulum during calcium signaling in sensory neurons.
Animals↗
Nonredundant roles of mitochondria-associated F-box proteins Mfb1 and Mdm30 in maintenance of mitochondrial morphology in yeast.
Mitochondria constantly fuse and divide to adapt organellar morphology to the cell's ever-changing physiological conditions. Little is known about the molecular mechanisms regulating mitochondrial dynamics. F-box proteins are subunits of both Skp1-Cullin-F-box (SCF) ubiquitin ligases and non-SCF complexes that regulate a large number of cellular processes. Here, we analyzed the roles of two yeast F-box proteins, Mfb1 and Mdm30, in mitochondrial dynamics. Mfb1 is a novel mitochondria-associated F-box protein. Mitochondria in mutants lacking Mfb1 are fusion competent, but they form aberrant aggregates of interconnected tubules. In contrast, mitochondria in mutants lacking Mdm30 are highly fragmented due to a defect in mitochondrial fusion. Fragmented mitochondria are docked but nonfused in Deltamdm30 cells. Mitochondrial fusion is also blocked during sporulation of homozygous diploid mutants lacking Mdm30, leading to a mitochondrial inheritance defect in ascospores. Mfb1 and Mdm30 exert nonredundant functions and likely have different target proteins. Because defects in F-box protein mutants could not be mimicked by depletion of SCF complex and proteasome core subunits, additional yet unknown factors are likely involved in regulating mitochondrial dynamics. We propose that mitochondria-associated F-box proteins Mfb1 and Mdm30 are key components of a complex machinery that regulates mitochondrial dynamics throughout yeast's entire life cycle.
Amino Acid Sequence↗
Instability of the mitofusin Fzo1 regulates mitochondrial morphology during the mating response of the yeast Saccharomyces cerevisiae.
Mitochondria form a highly dynamic network that is shaped by continuous fission and fusion of these organelles. In the yeast Saccharomyces cerevisiae two machineries are involved in this process, one of which includes the mitochondrial fusion promoting GTPase Fzo1. Although a role for the F-box protein Mdm30 in regulating the stability of Fzo1 has been proposed, the molecular basis for the regulation of the fission to fusion ratio of mitochondria remains unknown. To discern the mechanism of the regulation of mitochondrial morphology, we arrested cells at different stages of the cell cycle and examined mitochondrial morphology as well as the stability of mitochondrial fission and fusion proteins. In response to a G1 arrest evoked by the mating pheromone alpha factor the mitochondrial network fragmented into small pieces, which was accompanied by dramatic down-regulation of Fzo1. Mating pheromone also triggered the degradation of Fzo1 produced under the control of a constitutive promoter, and Fzo1 was stabilized upon proteasome inhibition, indicating a role for the proteasome system in the degradation of Fzo1. However, deletion of MDM30 did not stabilize Fzo1 after mating pheromone treatment, showing a different mechanism from the previously reported process of steady state Fzo1 regulation. We show an example for a regulated change of the mitochondrial fission to fusion ratio during the life cycle of budding yeast. Proteasomal degradation of Fzo1 in response to the mating pheromone is proposed to mediate the remodeling of the mitochondrial network during the process of mating.
Animals↗
Calcium signaling and apoptosis.
Ca(2+) is one of the key regulators of cell survival, but Ca(2+) can also induce apoptosis in response to a variety of pathological conditions. The pro-apoptotic effects of Ca(2+) are mediated by a diverse range of Ca(2+)-sensitive factors that are compartmentalized in various intracellular organelles including the ER, cytoplasm, and mitochondria. The Ca(2+) dynamics of these organelles appear to be modulated by the apoptosis-regulating Bcl-2 family proteins. In this paper, the recent progress of research on the mechanisms mediating the apoptosis-regulating effects of Ca(2+) and the interactions of Bcl-2 family proteins with the Ca(2+) storage organelles are discussed.
Animals↗
[Study of the mitochondria movement using videomicroscopy].
A stable cell line CV-1 was obtained for vital observation of the transport of mitochondria in animals cells, which express a fragment of the resident protein of mitochondria marked by yellow fluorescent protein. The parameters and conditions of movement of the mitochondria in living cells were established using fluorescence videomicroscopy. Under the normal conditions, only a small part of mitochondria (ca. 7%) was transported over significant distances, while others were in the state of relative rest. The effective transport of mitochondria strictly depended on the dynamic properties of microtubules. Incubation of cell in a serum-free medium suppressed active transport of mitochondria, thus suggesting its dependence on certain, not yet determined environmental factors.
Animals↗
Mitochondrial dynamics and division in budding yeast.
Mitochondria adopt a variety of different shapes in eukaryotic cells, ranging from multiple, small compartments to elaborate tubular networks. The establishment and maintenance of different mitochondrial morphologies depends, in part, on the equilibrium between opposing fission and fusion events. Recent studies in yeast, flies, worms and mammalian cells indicate that three high-molecular-weight GTPases control mitochondrial membrane dynamics. One of these is a dynamin-related GTPase that acts on the outer mitochondrial membrane to regulate fission. Recently, genetic approaches in budding yeast have identified additional components of the fission machinery. These and other new findings suggest a common mechanism for membrane fission events that has been conserved and adapted during eukaryotic evolution.
Cell Cycle↗
Mitochondrial signaling pathways: a receiver/integrator organelle.
Research over the last decade has extended the prevailing view of cell mitochondrial function well beyond its critical bioenergetic role in supplying ATP. Recently, it has been recognized that the mitochondria play a critical role in cell regulatory and signaling events, in the responses of cells to a multiplicity of physiological and genetic stresses, inter-organelle communication, cell proliferation and cell death. Nevertheless, a broad-based review on mitochondrial signaling is not presently available. To bridge that gap, this review examines the perspective of mitochondria as the receiver integrator and transmitter of signals, dissecting the multiple and interrelated signaling pathways at both the molecular and biochemical levels with particular focus on nuclear and cytoplasmic factors, fundamentally involved in the shaping of the organelles' responses. We examine evidence that the mitochondria act as a dynamic receiver and integrator of numerous translocated signaling proteins (including protein kinases and transcription factors), regulatory Ca2+ fluxes and membrane phospholipids as well the transmission of mitochondrial-generated oxidative stress and energy-related signaling. Novel experimental approaches studying mitochondrial signaling including cell studies using metabolic inhibitors and genetic stresses (e.g. mtDNA depletion) are discussed. While there is abundant interest and information concerning its integral role to apoptosis, mitochondrial signaling also plays a fundamental role in proliferative pathways, nutrient sensing, inter-organellar cross-talk and in the responses of cells to metabolic transition and physiological stresses which remain relatively unexplored.
Animals↗
Population dynamics of the 2 major mitochondrial DNA haplotypes in experimental populations of Drosophila subobscura.
The evolution of Drosophila subobscura mitochondrial DNA has been studied in experimental populations, founded with flies from a natural population from Calvià (Majorca, Balearic Islands, Spain). This population, like others founded in Europe, is characterized by the presence of 2 very common (>95%) mitochondrial haplotypes (named I and II) and rare and endemic haplotypes that appear at very low frequencies. Four experimental populations were established with flies having a heterogeneous nuclear genetic background, which was representative of the composition of the natural population. The populations were started with haplotypes I and II at an initial frequency of 50% each. After 33 generations, the 2 haplotypes coexisted. Random drift could be rejected as the only force responsible for the observed changes in haplotype frequencies. A slight but significant linear trend favouring a mtDNA (haploid) fitness effect has been detected, with a nonlinear deviation that could be due to a nuclear component. An analysis of chromosomal arrangements was made before the foundations of the cages and at generation 23. Our results indicated that the hypothesis that the maintenance of the frequencies of haplotypes I and II in natural populations could be due to their association with chromosomal arrangements remains controversial.
Animals↗
A human dynamin-related protein controls the distribution of mitochondria.
Mitochondria exist as a dynamic tubular network with projections that move, break, and reseal in response to local environmental changes. We present evidence that a human dynamin-related protein (Drp1) is specifically required to establish this morphology. Drp1 is a GTPase with a domain structure similar to that of other dynamin family members. To identify the function of Drp1, we transiently transfected cells with mutant Drp1. A mutation in the GTPase domain caused profound alterations in mitochondrial morphology. The tubular projections normally present in wild-type cells were retracted into large perinuclear aggregates in cells expressing mutant Drp1. The morphology of other organelles was unaffected by mutant Drp1. There was also no effect of mutant Drp1 on the transport functions of the secretory and endocytic pathways. By EM, the mitochondrial aggregates found in cells that were transfected with mutant Drp1 appear as clusters of tubules rather than a large mass of coalescing membrane. We propose that Drp1 is important for distributing mitochondrial tubules throughout the cell. The function of this new dynamin-related protein in organelle morphology represents a novel role for a member of the dynamin family of proteins.
Animals↗
The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function.
Primary lateral sclerosis (PLS) is a rare progressive paralytic disorder that results from dysfunction of the upper motoneurons. Although PLS is a sporadic disorder of adult middle age, it has also been described in children as juvenile PLS or JPLS. The causative gene for JPLS was found to be ALS2, which is also responsible for a recessive form of amyotrophic lateral sclerosis, for infantile onset ascending hereditary spastic paralysis (IAHSP) and for a form of complicated hereditary spastic paraplegia (cHSP). ALS2 gene encodes a protein termed alsin, containing multiple guanine nucleotide exchange factor domains, specifically binding to small GTPase Rab5 and acting as a GEF for Rab5. In vitrostudies performed with full-length and truncating forms of alsin protein support its role in endosomal dynamics and trafficking of mitochondria. All ALS2 mutations so far reported generate alsin protein truncation. Here, we describe the first homozygous missense mutation in ALS2, p.G540E. The mutation, which falls within the RCC1 domain, was identified in a 34-year-old patient with typical signs of JPLS such as ascending generalized and severe spasticity involving the limbs and the bulbar region, dysphagia, limb atrophy, preserved cognition and sensation. The father and two proband's sisters were found to be heterozygous carriers of the mutation with no signs of the disease. Studies in the neuronal cell line SK-N-BE indicated that the known subcellular localization of wild-type alsin with the early endosome antigen 1, in enlarged endosomal structures, and transferrin receptor is completely lost by the mutant protein, thus indicating that this mutation leads to protein delocalization. Mutant alsin induced neuronal death itself and also significantly enhanced the apoptogenic effect of NMDA and staurosporine. This effect was associated with decreased Bcl-xL : Bax ratio. In contrast, wild-type alsin was neuroprotective and increased Bcl-xL : Bax ratio. Our results provide the first demonstration that a missense mutation in alsin is cytotoxic. In addition, the identification of Bcl-xL/Bax as target of protection by alsin and of cytotoxicity by the mutant form provides a new signalling event regulated by alsin protein that may be important to define its role in neuronal physiology and neurodegeneration. Finally, the phenotype-genotype correlation in our patient, in view of all other ALS2 mutant cases reported previously, suggests a functional interplay of long and short forms of alsin in relation to disease onset and progression.
Adult↗
Store-operated calcium channels.
In electrically nonexcitable cells, Ca(2+) influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major Ca(2+) entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca(2+) stores activates Ca(2+) influx (store-operated Ca(2+) entry, or capacitative Ca(2+) entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca(2+) release-activated Ca(2+) current, I(CRAC). Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for I(CRAC)-like currents in excitable cells too. In spite of intense research, the signal that relays the store Ca(2+) content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca(2+) sensor within the stores, remains elusive. Resolution of these issues would be greatly helped by the identification of the CRAC channel gene. In some systems, evidence suggests that store-operated channels might be related to TRP homologs, although no consensus has yet been reached. Better understood are mechanisms that inactivate store-operated entry and hence control the overall duration of Ca(2+) entry. Recent work has revealed a central role for mitochondria in the regulation of I(CRAC), and this is particularly prominent under physiological conditions. I(CRAC) therefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of I(CRAC) and other store-operated Ca(2+) currents and how they are regulated, and we consider recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca(2+) entry pathway.
Animals↗