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At least 883 records · Page 49Linked to original sources
PubMed2004

Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome.

Sepsis is the leading cause of death in medical intensive care units. In most fatal cases of sepsis the patient experiences an insidious, progressive decline in vital organ function, i.e. multiple organ dysfunction syndrome (MODS), which is commonly associated with signs of accelerated anaerobic metabolism despite supernormal systemic oxygen delivery. Based on this clinical scenario, tissue hypoxia has long been considered the putative mechanism of MODS. However, efforts to enhance tissue oxygenation during severe sepsis have proved ineffective, and a growing body of evidence indicates that mitochondria contribute significantly to the pathogenesis of sepsis-induced MODS. In addition to dysregulation of oxygen metabolism ('cytopathic hypoxia'), sepsis-induced mitochondrial dysfunction contributes to organ injury through accelerated oxidant production and by promoting cell death. Advances in our understanding of the mechanisms of mitochondrial damage and in its detection could revolutionize the management of this devastating disease.

Journal Article↗
PubMedDate not supplied

Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro.

Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer's disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short-term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron-dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9-aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1-hydroxy and 7-hydroxy tacrine metabolites, acridine hydrochloride and acridine 9-carboxylic acid, and the non-acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine-like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes.

Acridines↗
PubMed1997

Aging and caloric restriction affect mitochondrial respiration and lipid membrane status: an electron paramagnetic resonance investigation.

Previous studies have indicated that reactive oxygen species (ROS) are likely involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). ROS, generated by succinate-stimulated mitochondria, have been reported to be spin trapped and detected by electron paramagnetic resonance (EPR). Our aim in the current study was to study the impact of aging on the effect of increased metabolic stimuli on mitochondrial respiration in terms of oxy-radical generation and possible lipid peroxidative changes in brain neocortical membranes. A mixed population of brain synaptosomes and mitochondria from brown norway male rats of differing ages being fed either ad lib (AL) or a caloric-restricted diet (DR) was prepared and labeled with 5-nitroxyl stearate (5-NS), a membrane lipid-specific spin label. The changes in anisotropic motion of the intercalated 5-NS spin probe also allows one to evaluate the status of the membrane fluidity in the lipid microenvironment via the order parameter. Upon succinate stimulation of mitochondria, the ROS generated resulted in a decrease in the EPR signal amplitude of the 5-NS reporter molecule indicative of the flux of oxy-radicals produced and possible peroxidation-induced changes in the synaptosomal lipid membrane. The line width remained constant, indicating that the overall intensity was reduced. The results showed a significant overall age effect in the ability to generate oxygen-derived radicals following metabolic stimulation (p < .0001). Stimulation of state 4 mitochondrial respiration with 20 mM succinate resulted in greater oxy-radical production in 25-month-old animals as compared to younger animals, suggesting increased mitochondrial leakage with age. Free radical stress induced by metabolic stimulation also causes a concomitant increase in membrane fluidity (p < .0001). There was also a significant age effect (p < .0007) on the order parameter of the mixed population of membranes. Although caloric restriction attenuated the membrane rigidization caused by aging, it was found to play a role in limiting the oxy-radical production following metabolic stimulation of mitochondria. The overall effect of age on membrane spin-label intensities EPR signal upon succinate stimulation suggests that progressive mitochondrial dysfunction may be a key factor in the aging process and in development of age-associated diseases.

Aging↗
PubMedDate not supplied

Hyperthyroid myopathy with mitochondrial paracrystalline rectangular inclusions.

The ultrastructural features of a case of severe hyperthyroid myopathy are presented. Along with the moderate increase in mitochondrial size and number usually observed in most patients with hyperthyroid myopathy, some of the skeletal muscle mitochondria in the present case also contained paracrystalline rectangular inclusions. This finding has not been previously reported in hyperthyroid myopathy and further supports the current view that mitochondrial abnormalities play a major role in the pathogenesis of muscle dysfunction in hyperthyroid patients.

Aged↗
PubMed1995

Morphological alterations in neocortical and cerebellar GABAergic neurons in a canine model of juvenile Batten disease.

The pathogenesis of brain dysfunction in a canine model of juvenile Batten disease was studied with techniques designed to determine sequential changes in mitochondrial morphology and cytochrome oxidase (CO) activity, and in neurons and synapses using gamma-aminobutyric acid (GABA) as a neurotransmitter. Histochemical and immunocytochemical methods were employed. Mitochondrial alterations were found in a select population of nonpyramidal neurons in neocortex and claustrum, and in cerebellar basket cells. Proportions of affected neurons at any one time remained constant over the disease course, with morphologically-abnormal mitochondria first being recognized at age 6 months. Enlarged mitochondria were readily identifiable at the light microscope (LM) level as large CO-positive or mitochondrial antibody-positive granular structures. Colabelling with antibodies to GABA or to parvalbumin (PV) indicated that most of these cells were GABAergic. Ultrastructurally, atypical mitochondria were characterized by globular enlargement, intramitochondrial membranous inclusions, and disorganized internal structure. CO activity in all other cell somata and in neuropil was diminished compared with normal, age-matched tissue. Glutamic acid decarboxylase (GAD), PV, and GABA studies demonstrated loss of GABAergic neurons and synapses in cortex and cerebellum of affected dogs. These results indicate that abnormal mitochondria are present in neurons in Batten disease, and suggest that suboptimal mitochondrial function may play a role in the pathogenic mechanisms of brain dysfunction in this disorder.

Animals↗
PubMed2006

Expanding insights of mitochondrial dysfunction in Parkinson's disease.

The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.

Animals↗
PubMed2001

Frataxin expression rescues mitochondrial dysfunctions in FRDA cells.

Friedreich's ataxia (FRDA) is the result of mutations in the nuclear-encoded frataxin gene, which is expressed in mitochondria. Several lines of evidence have suggested that frataxin is involved in mitochondrial iron homeostasis. We have transfected the frataxin gene into lymphoblasts of FRDA compound heterozygotes (FRDA-CH) with deficient frataxin expression to produce FRDA-CH-t cells in which message and protein are rescued to near-physiological levels. FRDA-CH cells were more sensitive to oxidative stress by challenge with free iron, hydrogen peroxide and the combination, consistent with a Fenton chemical mechanism of pathophysiology, and this sensitivity was rescued to control levels in FRDA-CH-t cells. Iron challenge caused increased mitochondrial iron levels in FRDA-CH cells, and a decreased mitochondrial membrane potential (MMP), both of which were rescued in FRDA-CH-t cells. The rescue of the low MMP, and high mitochondrial iron concentration by frataxin overexpression suggests that these cellular phenotypes are relevant to the central pathophysiological process in FRDA which is aggravated by exposure to free iron. However, even at physiological iron concentrations, FRDA-CH cells had decreased MMP as well as lower activities of aconitase and ICDH (two enzymes supporting MMP), and twice the level of filtrable mitochondrial iron (but no increase in total mitochondrial iron), and the observed phenotypes were either fully or partially rescued in FRDA-CH-t cells. Free iron is known to be toxic. The observation that frataxin deficiency (either directly or indirectly) causes an increase in filtrable mitochondrial iron provides a new hypothesis for the mechanism of cell death in this disease, and could be a target for therapy.

Aconitate Hydratase↗
PubMed2006

Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione peroxidase.

The cardiac toxicity of doxorubicin (DOX), a potent anticancer anthracycline antibiotic, is believed to be mediated through the generation of reactive oxygen species (ROS) in cardiomyocytes. This study aims to determine the function of cellular glutathione peroxidase (Gpx1), which is located in both mitochondria and cytosol, in defense against DOX-induced cardiomyopathy using a line of transgenic mice with cardiac overexpression of Gpx1. The Gpx1-overexpressing hearts were markedly more resistant than nontransgenic hearts to DOX-induced acute functional derangements, including impaired contractility and diastolic properties, decreased coronary flow rate, and reduced heart rate. In addition, DOX treatment impairs mitochondrial function of nontransgenic hearts as evident in a decreased rate of NAD-linked State 3 respiration, presumably a result of inactivation of complex I activity. This is associated with increases in the rates of NAD- and FAD-linked State 4 respiration and declines in P/O ratio, suggesting that the electron transfer and oxidative phosphorylation are uncoupled in these mitochondrial samples. These functional deficits of mitochondria could be largely prevented by Gpx1 overexpression. Taken together, these studies provide new evidence to further support the role of ROS, particularly H(2)O(2) and/or fatty acid hydroperoxides, in causing contractile and mitochondrial dysfunction in mouse hearts acutely exposed to DOX.

Animals↗
PubMed1987

[Relation between glutamate and adenine nucleotide levels of heart mitochondria during hypoxia].

The effect of acute respiratory hypoxia in rats on mitochondrial respiration, adenine nucleotides and some amino acids of the heart was studied. The decrease in the total (ATP + ADP + AMP) and exchangeable (ATP + ADP) adenine nucleotide pool of the mitochondria was accompanied by a pronounced loss of state 3 respiration with glutamate plus malate and a slight decrease with succinate plus rothenone. The uncoupled respiration of mitochondria with glutamate and malate was decreased in the same degree as in the absence of 2,4-dinitrophenol. State 4 respiration with substrates of both types was unaffected by hypoxia. These data point to a hypoxia-induced impairment of complex I of the respiratory chain. The decrease of tissue and mitochondrial glutamate was accompanied by the elevation of alanine content in the heart and an increase in intramitochondrial aspartate. The ADP-stimulated respiration of mitochondria was correlated with mitochondrial glutamate and ATP as well as with exchangeable adenine nucleotide pools during hypoxia. The experimental results suggest that mitochondrial dysfunction induced by hypoxia may also be attributed to the low level of mitochondrial glutamate.

Adenine Nucleotides↗
PubMed2006

Suppression of apoptosis by cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells.

The permeability transition pore is involved in the mitochondrial pathway of apoptosis. Cyclophilin D, a pore component, has catalytic activity as a peptidyl prolyl cis, trans-isomerase (PPIase), which is essential to the pore opening. It has been reported that cyclophilin D overexpression suppresses apoptosis in cancer cells. To clarify the mechanism of this effect, we generated glioma cells overexpressing wild-type or a PPIase-deficient mutant of cyclophilin D. Interestingly, we found that the PPIase-dependent apoptosis suppression by cyclophilin D correlated with the amounts of mitochondrial-bound hexokinase II, which has anti-apoptotic activity. Inactivation of endogenous cyclophilin D by small interference RNA or a cyclophilin inhibitor was found to release hexokinase II from mitochondria and to enhance Bax-mediated apoptosis. The anti-apoptotic effects of cyclophilin D were canceled out by the detachment of hexokinase II from mitochondria, demonstrating that mitochondrial binding of hexokinase II is essential to the apoptosis suppression by cyclophilin D. Furthermore, cyclophilin D dysfunction appears to abrogate hexokinase II-mediated apoptosis suppression, indicating that cyclophilin D is required for the anti-apoptotic activity of hexokinase II. Based on the above, we propose here that cyclophilin D suppresses apoptotic cell death via a mitochondrial hexokinase II-dependent mechanism in cancer cells.

Animals↗
PubMedDate not supplied

Neuronal ageing from an intraneuronal perspective: roles of endoplasmic reticulum and mitochondria.

The nature of brain ageing and the age-dependent decline in cognitive functions remains poorly understood. Physiological brain ageing is characterised by mild mental dysfunctions, whereas age-dependent neurodegeneration, as illustrated by Alzheimer disease (AD), results rapidly in severe dementia. These two states of the aged brain, the physiological and the pathological, are fundamentally different as the latter stems from significant neuronal loss, whereas the former develops without significant neuronal demise. In this paper, we review the changes in neuronal Ca(2+) homeostasis that occur during brain ageing, and conclude that normal, physiological ageing is characterised mainly by a decrease of neuronal homeostatic reserve, defined as the capacity to respond effectively to functional and metabolic stressors, but does not reach the trigger required to induce neuronal death. In contrast, during neurodegenerative states, Ca(2+) homeostasis is affected early during the pathological process and result in significant neuronal demise. We also review recent evidence suggesting that the endoplasmic reticulum (ER) might play an important role in controlling the balance between healthy and pathological neuronal ageing.

Adenosine Triphosphate↗
PubMed1999

Progress on the mitochondrial permeability transition pore: regulation by complex I and ubiquinone analogs.

This review summarizes recent progress on the regulation of the mitochondrial permeability transition pore, an inner membrane channel that may play a role in cell death. We briefly cover its key control points as emerged over the last few years from studies on isolated mitochondria; and describe in some detail our recent results indicating that the pore is modulated by the respiratory chain complex I and can be specifically blocked by selected ubiquinone analogs. We discuss the potential relevance of these findings for the structural definition of the permeability transition pore and illustrate the pharmacological perspectives they offer in diseases where mitochondrial dysfunction is suspected to play a key role.

Animals↗
PubMed1999

Molecular pathogenesis of Friedreich ataxia.

Friedreich ataxia, the most common type of inherited ataxia, is itself caused in most cases by a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene. The autosomal recessive inheritance of the disease gives this triplet repeat mutation some unique features of natural history and evolution. Frataxin is a mitochondrial protein that has homologues in yeast and even in gram-negative bacteria. Yeast organisms deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich ataxia is caused by mitochondrial dysfunction and free radical toxicity.

Friedreich Ataxia↗