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At least 19 recordsLinked to original sources
PubMed1980

Ultrastructural study of globular inclusions in human skeletal muscle mitochondria.

Limb muscle biopsies from a patient with Luft's disease and a patient with a slowly progressive neuromuscular disorder since infancy revealed by conventional electron microscopy the presence of globular inclusions in the mitochondria as one of the most prominent morphological findings. Electron cytochemical studies on fresh tissue blocks showed no cytochrome c oxidase activity within the globular inclusions. The study of strontium uptake supported by either NAD and flavo-protein linked substrates in freshly isolated mitochondria fractions showed no electron-dense needles within the globular inclusions. Attempts to remove the inclusions with pepsin and with pronase on ultrathin sections failed but they were partially and totally removed by treatment of the sections with hydrogen peroxide. Freeze fracture studies showed the globular inclusions consisted of amorphous and lamellar material. The results suggest that the globular inclusions in muscle mitochondria may consist primarily of lipid.

Freeze Fracturing↗
PubMed1989

The role of calcium in the control of respiration by muscle mitochondria.

In muscle, energy supply is finely tuned to energy demand. Ca2+-activated ATP hydrolysis in the cytosol provides ADP to the mitochondrion to stimulate oxidative phosphorylation by acceptor control of mitochondrial respiration. Although mitochondria are responsive to increased concentrations of ADP in vitro, oxygen extraction in cardiac muscle may increase independently of any significant alterations in cellular ADP levels or of dramatic changes in cellular phosphate metabolites as determined by P-31 NMR. Alterations in ATP/ADP ratios in skeletal muscle with aerobic exercise may be dependent on fiber type, with maintained ATP levels seen in oxidative fibers during muscle work. These data are consistent with increased rates of NADH generation by mitochondrial dehydrogenases, so that ATP production keeps pace with ATP hydrolysis in the cytosol. The mechanism of increased ATP synthesis in muscle mitochondria is termed "stimulus-response-metabolism coupling." Ca2+ ion increases in the muscle cytosol enhance contractility and glycogen breakdown. The Ca2+ signal is then transmitted to the mitochondria to provide matrix Ca2+ concentrations, which activate Ca2+-sensitive dehydrogenase activities, leading to accelerated rates of NAD reduction and oxidative phosphorylation. Thus, Ca2+ signaling to the mitochondria may explain the lack of dramatic fluctuations in the cytosolic phosphorylation potential over a large range of contractile activities in cardiac muscle.

Animals↗
PubMed1980

Mechanisms of respiration and phosphorylation in Ascaris muscle mitochondria.

In Ascaris muscle mitochondria the major respiratory chain-linked phosphorylation activity is accomplished by a NADH-linked reduction of fumarate to succinate. Oxygen can also be employed as a terminal electron acceptor via a cyanide- and salicyl-hydroxamate-resistant terminal oxidase. As in fumarate-dependent electron transport this process appears to be coupled to energy conservation at phosphorylation site I. The branchpoint from which electrons are taken from the main respiratory chain to either the alternative oxidase or fumarate reductase is likely to be on the oxygen side of the NADH dehydrogenase segment. Malate and succinate are the only substrates which appreciably support respiration in the mitochondrion of the nematode. Regardless of the presence or absence of oxygen malate is utilized by an oxidation-reduction reaction resulting in the formation of pyruvate, acetate, succinate, propionate and CO2. In addition, aerobically, hydrogen peroxide is formed as the product of oxygen reduction. Succinate accumulation was found to be significantly higher in the anaerobic as compared to the aerobic incubation mixtures. This effect was accompanied by an increase in anaerobic malate consumption. ATP generation and the formation of pyruvate, acetate and propionate were found to be similar in the presence and absence of oxygen. In malate-supported respiration of intact Ascaris mitochondria reducing equivalents (NADH) are produced exclusively through pyruvate and acetate formation. These enzymatic reactions are functionally coupled to the electron transport-linked reductions of fumarate to succinate and oxygen to hydrogen peroxide, respectively. In accordance with the position of the redox potentials of the fumarate/succinate and O2/H2O2 couples, anaerobic and aerobic respiration was found to be associated with relatively low energy conservation efficiencies. Thus one molecule of ATP was conserved per 2e- transferred to fumarate or oxygen, respectively. No evidence could be obtained for a significant activity of energy conservation sites II and III and electron transfer through the alternative oxidase pathway was shown not to be coupled to phosphorylation.

Adenosine Triphosphate↗
PubMed1985

The NADH oxidase system (external) of muscle mitochondria and its role in the oxidation of cytoplasmic NADH.

An exo-NADH oxidase system [NADH oxidase system (external)], effecting intact-mitochondrial oxidation of added NADH, was studied in pigeon heart mitochondria. Breast muscle mitochondria showed an equal specific activity of the system. The exo-NADH oxidase activity (200 micron mol of NADH/min per g of protein) equalled two-thirds of the State-3 respiratory activity with malate + pyruvate or one-seventh of the total NADH oxidase activity of heart mitochondria. The activity was not caused by use of proteinase in the preparation procedure and all measured parameters were very reproducible from preparation to preparation. The activity is therefore most likely not due to preparation artefacts. The exo-NADH oxidase system is present in all mitochondria in the preparation and is not confined to a subpopulation. The system reduced all cytochrome anaerobically and direct interaction with all cytochrome oxidase was demonstrated by interdependent cyanide inhibition. The exo-NADH oxidase system seems to be located at the outer surface of the mitochondrial inner membrane because, for instance, only this system was rapidly inhibited by rotenone, and ferricyanide could act as acceptor in the rotenone-inhibited system (reductase activity = 20 times oxidase activity). In the presence of antimycin, added NADH reduced only a part of the b-cytochromes. Freezing and thawing the mitochondria, one of the methods used for making them permeable to NADH, destroyed this functional compartmentation. The characteristics of the exo-NADH oxidase system and the malate-aspartate shuttle are compared and the evidence for the shuttle's function in heart in vivo is re-evaluated. It is proposed that oxidation of cytoplasmic NADH in red muscles primarily is effected by the exo-NADH oxidase system.

Animals↗
PubMed1978

Glutaminase activity in rat skeletal muscle mitochondria.

Isolated rat skeletal muscle mitochondria took up about 40-ng-atoms O per mg protein, with glutamine as the only respiratory substrate. The mitochondria incubated in the presence of glutamine and KCN formed both ammonia and glutamate in equivalent amounts. The experiments reported here provide suggestive evidence that rat skeletal muscle mitochondria contain glutaminase (L-glutamine amidohydrolase EC 3.5.1.2.) activity.

Ammonia↗
PubMed1980

Pyruvate carboxylase and propionyl-CoA carboxylase as anaplerotic enzymes in skeletal muscle mitochondria.

Oxygen uptake in skeletal muscle mitochondria respiring on pyruvate or on acetylcarnitine plus propionylcarnitine is stimulated 3--4-fold by bicarbonate. The stimulation is highly dependent on ATP. The respiration rate obtained amounts to 1/4-1/3 of the rate obtained with pyruvate-malate in the presence of ADP. With decreasing ATP/ADP ratios in the medium, a decreasing stimulation by bicarbonate is obtained. Similar results were obtained with heart mitochondria. With ATP added, a pyruvate-dependent build up of citric acid cycle intermediates takes place in incubations with skeletal muscle mitochondria amounting to about 0.5 nmol x min-1 x mg protein-1. In 14CO2-fixation experiments, the activity of pyruvate carboxylase (EC 6.4.2.1) amounts to about 3 nmol x min-1 x mg protein-1 under similar conditions. With propionylcarnitine plus acetylcarnitine a similar stimulation of respiration and fixation of bicarbonate is observed. In this case the respiration and the propionyl-CoA carboxylase (EC 6.4.1.3) is less inhibited by ADP. The results are discussed in relation to the regulation of the level of citric acid cycle intermediates in muscle tissues. It is concluded that pyruvate carboxylase is an important anaplerotic enzyme in skeletal muscle mitochondria.

Acetylcarnitine↗
PubMed1984

In vivo induced malignant hyperthermia in pigs. II. Metabolism of skeletal muscle mitochondria.

The biochemical characteristics of skeletal muscle mitochondria of malignant hyperthermia (MH) susceptible Dutch Landrace pigs have been investigated before and during an MH attack, induced in vivo by halothane plus succinylcholine. The muscle homogenates have a decreased capacity to synthesize ATP and creatine phosphate during the MH period. Muscle mitochondria prepared from susceptible pigs in an MH period consume less oxygen than do mitochondria isolated before the attack, or mitochondria from control pigs during the challenge. The oxidative phosphorylation is not uncoupled during the critical period. The production of CO2 indicates that the in vitro measured capacity of the MH muscle mitochondria correctly reflects the in vivo condition during the MH attack. The restricted synthesis may be caused by a factor, finding expression in the mitochondria themselves, and obtained or activated during the MH attack.

Adenosine Triphosphate↗
PubMed1982

Protonmotive force in muscle mitochondria.

The protonmotive force (delta p) of muscle mitochondria was measured by estimating the distribution of 14C-labeled TPMP (trimethylphenylphosphonium iodide) and 14C-labeled acetate across the inner membrane of muscle mitochondria. The matrix volume was simultaneously determined using 3H-labeled H2O and 3H-labeled mannitol and repeated drying to distinguish the label in these 2 compounds. Rapid separation of mitochondria from the incubation medium by centrifugation through silicone oil avoids the problems of potential anaerobic conditions associated with conventional centrifugation and large volumes of trapped media associated with filtration. The value for delta p (mean +/- SD) was 192+/- 26 mV in 30 determinations with rat muscle mitochondria during state 4. Measurement of oxygen consumption allowed calculation of membrane conductance (Cm,H+) which was 0.49 +/- 0.18 nmol of H+/min/mg protein/mV. The values for delta p and Cm,H+ are reported for a variety of experimental conditions and are consistent with Mitchell's chemiosmotic theory. Biopsy specimens obtained from human muscle gave state-4 delta p values of 197+/- 30 mV (n =5) and Cm,H+ values of 0.52 +/- 0.12 nmol of H+/min/mg/mV (n = 4). This delta p assay is the first described for coupled mammalian muscle mitochondria and will be useful in assessing membrane function.

Animals↗
PubMed2000

AMP decreases the efficiency of skeletal-muscle mitochondria.

Mitochondrial proton leak in rat muscle is responsible for approx. 15% of the standard metabolic rate, so its modulation could be important in regulating metabolic efficiency. We report in the present paper that physiological concentrations of AMP (K(0.5)=80 microM) increase the resting respiration rate and double the proton conductance of rat skeletal-muscle mitochondria. This effect is specific for AMP. AMP also doubles proton conductance in skeletal-muscle mitochondria from an ectotherm (the frog Rana temporaria), suggesting that AMP activation is not primarily for thermogenesis. AMP activation in rat muscle mitochondria is unchanged when uncoupling protein-3 is doubled by starvation, indicating that this protein is not involved in the AMP effect. AMP activation is, however, abolished by inhibitors and substrates of the adenine nucleotide translocase (ANT), suggesting that this carrier (possibly the ANT1 isoform) mediates AMP activation. AMP activation of ANT could be important for physiological regulation of metabolic rate.

Adenosine Monophosphate↗
PubMed1984

In vivo induced malignant hyperthermia in pigs. III. Localization of calcium in skeletal muscle mitochondria by means of electronmicroscopy and microprobe analysis.

Biceps femoris muscle biopsies of malignant hyperthermia susceptible (MH+) and non-susceptible (MH-) Dutch Landrace pigs were studied ultrastructurally, and exchangeable calcium was demonstrated, using the antimonate precipitation technique in combination with electron probe x-ray microanalysis. Biopsies were taken before and during the administration of halothane-plus-succinylcholine and after dantrolene sodium treatment of the animals. MH+ muscle, taken before the MH triggering, showed a high proportion (about 35%) of cells with supercontraction. Both MH+ and MH- muscle had broad but nearly identical ranges of cell diameter. Core-like structures were occasionally present in muscle from MH+ pigs. Muscle mitochondria from the MH+ pigs accumulated large amounts of calcium in their matrix compartment during the halothane-plus-succinylcholine induced MH crisis. This calcium loading in the course of time caused swelling and structural damage to the mitochondria. Skeletal muscle mitochondria from MH- pigs did not show such a reaction pattern on challenge with halothane and succinylcholine. It is concluded that in MH+ pigs the challenge brings about an increase in myoplasmic free calcium, which is predominantly due to calcium influx from the extracellular fluid. This rise in cytosolic calcium causes the mitochondria to accumulate the cation in an energy-dependent way. These findings are discussed in relation to the diverging halothane and caffeine contraction responses of aerobic type I and anaerobic type II muscle fibres.

Animals↗
PubMed1980

The histochemical characterization of the coupling state of skeletal muscle mitochondria.

Isolated mitochondria from skeletal muscles of human and animals with neuromuscular diseases may reveal a loosely coupled state of oxidative phosphorylation, which is characterized by a normal phosphorylation in the presence of a phosphate acceptor and a maximal respiration in the absence of a phosphate acceptor. Moreover in these cases activity of mitochondrial Mg2+-stimulated ATPase is strongly increased and cannot be stimulated by the uncoupler 2,4-dinitrophenol. In this communication a histochemical technique for the demonstration of activity of mitochondrial Mg2+-stimulated ATPase to characterize the coupling state of muscle mitochondria in tissue sections, is described. This tissue-saving technique is especially suitable for the study of human skeletal muscle diseases.

Adenosine Triphosphatases↗
PubMed2003

Plasticity of skeletal muscle mitochondria: structure and function.

Mitochondria in skeletal muscle tissue can undergo rapid and characteristic changes as a consequence of manipulations of muscle use and environmental conditions. Endurance exercise training leads to increases of mitochondrial volume of up to 50% in training interventions of a few weeks in previously untrained subjects. Additionally, a shift of substrate metabolism toward a higher reliance on lipids is observed, structurally reflected as a doubling of the intramyocellular lipid content. A similar increase in intramyocellular lipids without an increase in mitochondrial volume is observed as a consequence of a high-fat diet. Strength training has a major impact on muscle myofibrillar volume, however the mitochondrial compartment appears relatively unchanged. Bedrest and microgravity conditions lead to losses of both myofibrillar and mitochondrial volume, likely as a consequence of the decrease in metabolic and mechanical stress on muscle tissue. Permanent severe hypoxia leads to a loss of muscle mass and muscle oxidative capacity; however, hypoxia signaling events are triggered, which lead to distinct reprogramming phenomena of the transcriptome of the muscle cells. The molecular mechanisms that orchestrate the plasticity of skeletal muscle mitochondria are just beginning to unfold. The present data indicate that transcriptional events largely contribute to increases in mitochondrial mass in human skeletal muscle with endurance training. Expression of mitochondrial proteins from the nuclear and mitochondrial genomes is coordinated and involves the nuclear-encoded transcription factors NRF-1 and TFAM. Transcription of genes encoding the mitochondrial proteins involved in beta oxidation can be regulated separately from the genes of the Krebs cycle and the respiratory chain. Transcription factors AP-1 and PPARalpha/gamma and the protein kinase AMPK are signaling molecules that transduce the metabolic and mechanical factors sensed during endurance training into the complex transcriptional adaptations of mitochondrial proteins.

Adaptation, Physiological↗
PubMed1976

Monamine oxidase in outer membrane of skeletal muscle mitochondria.

(1) Monoamine oxidase (EC 1.4.3.4) is present in rat skeletal muscle mitochondria. (2) A radioassay procedure for the assay of monoamine oxidase in muscle mitochondria is described. It is based on teh procedure using side-chain [2-14C]-tryptamine as substate described by Wurtman, R.J. and Axelrod, J. (1963) Biochem. Pharmacol. 12, 1439--1441 and employs a pH of 8.0 and a substrate concentration of 0.25 mM. (3) The Km of the muscle mitochondrial enzyme at pH 8.0 is 1.34 - 10(-5) M and that of the liver enzyme under the same conditions is 2.5 - 10(-5) M. Muscle mitochondria contain only one quarter of the activity of enzyme present in liver mitochondria. (4) Monoamine oxidase is shown to be in the outer membrane of skeletal muscle mitochondria and thus to be a suitable marker enzyme for use in the fractionation of these mitochondria.

Animals↗