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Results for “Mitochondria dysfunction”

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At least 649 records · Page 36Linked to original sources

PubMed2005

Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-B-crystallin desmin-related cardiomyopathy.

BACKGROUND: Mitochondria and sarcomeres have a well-defined architectural relation that partially depends on the integrity of the cytoskeletal network. An R120G missense mutation in the small heat shock protein alpha-B-crystallin (CryAB) causes desmin-related cardiomyopathy. Desmin-related cardiomyopathy is characterized by the formation of intracellular aggregates containing CryAB and desmin that are amyloid positive, and disease can be recapitulated in transgenic mice by cardiac-specific expression of the mutant protein. METHODS AND RESULTS: To understand the resultant pathology, we explored the acute effects of R120G expression both in vitro and in vivo. In vitro, transfection of adult cardiomyocytes with R120G-expressing adenovirus resulted in altered contractile mechanics. In vivo, as the cytoskeletal network is disturbed but before deficits in organ function can be detected, alterations in mitochondrial organization and architecture occur, leading to a reduction in the maximal rate of oxygen consumption with substrates that utilize complex I activity, alterations in the permeability transition pore, and compromised inner membrane potential. Apoptotic pathways are subsequently activated, which eventually results in cardiomyocyte death, dilation, and heart failure. CONCLUSIONS: Cardiac chaperone dysfunction acutely leads to altered cardiomyocyte mechanics, perturbations in mitochondrial-sarcomere architecture, and deficits in mitochondrial function, which can result in activation of apoptosis and heart failure.

Amyloid↗

PubMed1999

Absence of mitochondrial dysfunction in polymyalgia rheumatica. Evidence based on a simultaneous molecular and biochemical approach.

OBJECTIVE: To investigate the molecular and biochemical profile of skeletal muscle mitochondria of patients with isolated polymyalgia rheumatica (PMR). PATIENTS AND METHODS: We included patients with a recent diagnosis of PMR and as control healthy individuals submitted to orthopedic surgery. Skeletal muscle was obtained from quadriceps, thus was mitochondria immediately isolated. Long polymerase chain reaction and Southern blot transference were performed to detect deleted mtDNA molecules. Mitochondrial oxidative activity using different substrates and individual enzyme activity of respiratory chain complexes were assessed to search for any biochemical dysfunction. RESULTS: Fifty-one individuals (PMR=25, controls=26) were included. Mean age was 72 (11) years; 45% were females. We found no significant increase of deleted mtDNA molecules in PMR patients compared to controls. Both groups differed neither on oxygen consumption (p=NS for all substrates) nor enzymatic activity (p=NS for all complexes). CONCLUSIONS: Skeletal muscle mitochondria are molecularly and biochemically unaffected in PMR.

Adenosine Triphosphatases↗

PubMed2001

How understanding the control of energy metabolism can help investigation of mitochondrial dysfunction, regulation and pharmacology.

Understanding the control of mitochondrial energy metabolism is central to knowing how mitochondria function within cells. Metabolic control analysis is the best approach available for studying the control of mitochondrial energy metabolism. Here I outline how metabolic control analysis has been used to help understand mitochondrial regulation, damage and pharmacology.

Adenosine Triphosphate↗

PubMed2007

Melatonin role in the mitochondrial function.

Melatonin is an ancient molecule present in unicellular organisms at the very early moment of life. Initially identified as a secretory product of the pineal gland in mammals and in other species, it was considered a hormone related to reproduction. The evidence that melatonin is produced in many organs and tissues of the body, reaching concentrations higher than in the blood, support the multiplicity of the melatonin actions. The best-known actions of melatonin, currently supported by experimental and clinical data, include antioxidant and anti-inflammatory abilities, some of them involving genomic regulation of a series of enzymes. Besides, melatonin displays anticonvulsant and antiexcitotoxic properties. Most of the beneficial consequences resulting from melatonin administration may depend on its effects on mitochondrial physiology. The physiological effects of melatonin on normal mitochondria, its role to prevent mitochondrial impairment, energy failure, and apoptosis in oxidatively-damaged mitochondria, and the beneficial effects of the administration of melatonin in experimental and clinical diseases involving mitochondrial dysfunction and cell death, are revised.

Animals↗

PubMed2001

Mitochondria as subcellular targets for clinically useful anthracyclines.

Due to the widespread use of anthracyclines as antitumor agents, a large number of investigations have been reported analyzing clinical and molecular aspects of these quinone antibiotics. While the high affinity of anthracyclines towards chromosomal DNA has been held responsible for their antitumor activity, an increasing amount of data is being accumulated showing that these drugs also target mitochondria thus interfering with major mitochondrial functions. Since this toxicity of anthracyclines towards mitochondria is associated with side effects significantly limiting their chemotherapeutic dose, the corresponding underlying mechanisms need to be understood. Bioenergetic failure, enzyme inhibitions, lipid peroxidations, induction of membrane disorders as well as the initiation of oxidative stress are being attributed to the accumulation of anthracyclines at or inside mitochondria. In this review the wide spectrum of possible mode of actions of these antibiotics leading to mitochondrial dysfunctions will be presented and discussed.

Antibiotics, Antineoplastic↗

PubMed2005

[Mitochondrial dysfunction in bipolar disorder].

Phosphorus magnetic resonance spectroscopic studies in bipolar disorder revealed altered brain energy metabolism resembling that of chronic progressive external ophthalmoplegia (CPEO). Mood disorder is one characteristic symptom in several families of CPEO caused by mutations of three genes, ANT1, Twinkle, and POLG. Molecular genetic analysis revealed association of bipolar disorder with mitochondrial DNA (mtDNA) 10398A polymorphism, 3644C mutation, and FDUFV2. In the postmortem brains, increased levels of mtDNA 4977bp deletion and 3243G mutation, and altered expression of mitochondria-related genes were reported. Mitochondria play an important role in neuroplasticity and apoptotic signaling via regulating intracellular calcium homeostasis. Thus, mitochondrial dysfunction may cause altered calcium homeostasis and neuroplasticity, resulting in bipolar disorder. Most molecular genetic findings in bipolar disorder regarding mitochondria and endoplasmic reticulum stress signaling are common to Parkinson's disease and diabetes mellitus. Thus, it is possible that bipolar disorder is also a disease caused by the progressive loss of some neuronal cells.

Bipolar Disorder↗

PubMed2002

Gastric irritant-induced apoptosis in guinea pig gastric mucosal cells in primary culture.

When the gastric mucosa is exposed to various irritants, apoptosis and subsequent gastric mucosal lesion can result in vivo. We here show that gastric irritants induced apoptosis in gastric mucosal cells in primary culture and examined its molecular mechanism. Ethanol, hydrogen peroxide, and hydrochloric acid all induced, in a dose-dependent manner, cell death, apoptotic DNA fragmentation, and chromatin condensation, suggesting that each of these gastric irritants induced apoptosis in vitro. Since each of these irritants decreased the mitochondrial membrane potential and stimulated the release of cytochrome c from mitochondria, gastric irritant-induced apoptosis seems to be mediated by mitochondrial dysfunction. Caspase-3, caspase-8, and caspase-9-like activities were all activated simultaneously by each of these irritants and the activation was concomitantly with cell death and apoptotic DNA fragmentation. Furthermore, pre-treatment of gastric mucosal cells with an inhibitor of caspase-8 suppressed the onset of cell death as well as the stimulation of caspase-3- and caspase-9-like activities caused by each of these gastric irritants. Based on these results, we consider that caspase-8, an initiator caspase, plays an important role in gastric irritant-induced apoptosis.

Animals↗

PubMed1996

Assessment of the distribution of mitochondrial ribosomal RNA in melas and in thrombotic cerebral infarcts by in situ hybridization.

In situ hybridization to mitochondrial ribosomal RNA (rRNA) has been used to study the distribution of mitochondria in paraffin-embedded autopsy brain tissue from two patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and other organs from one of the patients. Comparison of in situ hybridization and electron microscopic findings in an antemortem biopsy specimen of pylorus from the latter patient showed a close correspondence between the distribution of hybridization signal on light microscopy and of mitochondria in ultrathin sections. Strong hybridization signal was present over smooth muscle fibres of the muscularis externa, which contained abnormal accumulations of mitochondria on electron microscopy. Hybridization to sections of skeletal muscle confirmed previous reports of 'ragged-red' fibres in this disorder and of mitochondrial accumulations in the walls of intramuscular blood vessels. To try to elucidate the role of vessel wall accumulation of mitochondria in the genesis of the stroke-like lesions, the distribution of mitochondrial rRNA was assessed in sections of brain from both of the cases of MFLAS and several cases of atherothrombotic cerebrovascular disease. Blood vessels in and adjacent to the cerebral lesions of MELAS showed strong hybridization signal with the mitochondrial probes, as was also seen in infarcts of various ages in the control brains. Only weak signal was present in the walls of blood vessels distant from the lesions, in both MELAS and control brains. These findings suggest that mitochondria accumulate in vascular endothelium and tunica media as a normal response to cerebral infarction or ischaemia. The accumulation of mitochondria in the cerebral lesions of MELAS may, at least in part, be a reaction to the destructive effects of the underlying metabolic dysfunction.

Brain↗

PubMed2004

Mitochondrial pathway is involved in hydrogen-peroxide-induced apoptotic cell death of oligodendrocytes.

Oligodendrocytes, the myelin-forming cells of the CNS, are specifically sensitive to oxidative stress and respond by the onset of programmed cell death (PCD). To further unravel the molecular events underlying their enhanced susceptibility, we have investigated whether mitochondrial damage occurs during oxidative stress-induced PCD in cultured rat brain oligodendrocytes. Mitochondria are considered as a central control point of apoptosis, and mitochondrial dysfunction has been linked to neurodegenerative disease. Upon a number of stimuli through the release of cytochrome c, they coordinate caspase activation, causing morphological and biochemical changes associated with PCD. Oxidative stress was exerted by the application of hydrogen peroxide. The data show that hydrogen peroxide-induced apoptosis in oligodendrocytes involves mitochondrial damage and cytochrome c release and is accompanied by the activation of the death-related caspases 3 and 9. Concomitantly, the activation and nuclear translocation of extracellular signal regulated kinases ERK1,2 are observed, which have been implicated to participate in the regulation of cell death and survival. DNA fragmentation could not be attenuated by the ERK1,2 inhibitor PD 98059, indicating that the ERK1,2- pathway in oligodendrocytes may be involved in the initial survival response after exposure to stressful stimuli.

Animals↗

PubMed2002

Impact of diabetes on induction of the mitochondrial permeability transition.

Diabetes is one of the most common metabolic diseases of our times. Specific cardiovascular alterations are often associated with the progression of this disease. Considerable controversy exists in the literature concerning the greater or lesser susceptibility of the diabetic heart to ischemia and reperfusion. Cardiac mitochondria may be fundamental to the differential susceptibility of the cardiomyocyte to pathologic phenomena, particularly those due to the induction of the degenerative process known as the mitochondrial permeability transition (MPT), which is triggered by excessive mitochondrial calcium accumulation. The MPT has been associated with cellular dysfunction resulting from ischemia and reperfusion. The objective of this work was to examine the susceptibility of mitochondria isolated from diabetic rats to the MPT, in comparison to healthy control rats of the same age. Cardiac mitochondria from the diabetic rats had higher calcium loading capacity before the development of the MPT, with a decreased incidence of MPTP-associated features. This was associated with a greater capacity to sustain multiple pulses of externally added calcium, simultaneously with maintenance of the transmembrane electrical potential and reduced swelling amplitude. This could mean that cardiomyocytes from diabetic hearts may indeed be less prone to dysfunctions resulting from ischemia and reperfusion, at least in milder diabetic conditions, thus explaining many reports in the literature.

Animals↗

PubMed2001

Interaction theory of mammalian mitochondria.

We generated mice with deletion mutant mtDNA by its introduction from somatic cells into mouse zygotes. Expressions of disease phenotypes are limited to tissues expressing mitochondrial dysfunction. Considering that all these mice share the same nuclear background, these observations suggest that accumulation of the mutant mtDNA and resultant expressions of mitochondrial dysfunction are responsible for expression of disease phenotypes. On the other hand, mitochondrial dysfunction and expression of clinical abnormalities were not observed until the mutant mtDNA accumulated predominantly. This protection is due to the presence of extensive and continuous interaction between exogenous mitochondria from cybrids and recipient mitochondria from embryos. Thus, we would like to propose a new hypothesis on mitochondrial biogenesis, interaction theory of mitochondria: mammalian mitochondria exchange genetic contents, and thus lost the individuality and function as a single dynamic cellular unit.

Animals↗

PubMed2005

Molecular aspects of atherogenesis: new insights and unsolved questions.

The development of atherosclerotic disease results from the interaction between environment and genetic make up. A key factor in atherogenesis is the oxidative modification of lipids, which is involved in the recruitment of mononuclear leukocytes to the arterial intima--a process regulated by several groups of adhesion molecules and cytokines. Activated leukocytes, as well as endothelial mitochondria, can produce reactive oxygen species (ROS) that are associated with endothelial dysfunction, a cause of reduced nitric oxide (NO) bioactivity and further ROS production. Peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR) are nuclear receptors significantly involved in the control of lipid metabolism, inflammation and insulin sensitivity. Also, an emerging role has been suggested for G protein coupled receptors and for the small Ras and Rho GTPases in the regulation of the expression of endothelial NO synthase (eNOS) and of tissue factor, which are involved in thrombus formation and modulation of vascular tone. Further, the interactions among eNOS, cholesterol, oxidated LDL and caveola membranes are probably involved in some molecular changes observed in vascular diseases. Despite the relevance of oxidative processes in atherogenesis, anti-oxidants have failed to significantly improve atherosclerosis (ATS) prevention, while statins have proved to be the most successful drugs.

Animals↗

PubMed2007

Brain nitric oxide synthases and mitochondrial function.

Nitric oxide is a small signaling molecule, which may act as a neurotransmitter and neuromodulator, exerting a regulatory effect on neuronal function. It can diffuse from its site of synthesis to different intra and extracellular compartments, being therefore present in the pre-synaptic, synaptic and post-synaptic spaces. Recently, a NOS located in the mitochondria (mtNOS) has been observed in different brain regions, responsible for the production of NO in these organelles and identified as nNOS. A regulatory effect of NO on mitochondrial function was described in brain mitochondria, where NO acts mainly by inhibiting cytochrome oxidase activity. Hippocampal mitochondrial dysfunction and decreased mtNOS activity and expression were reported in association with ultrastructural damage in an experimental model of hepatic encephalopathy. Enriched environment exposure preserved the aged animals from spatial cognition impairment; also environment and training modulated neuronal plasticity in pre-pubertal rats through NO-dependent mechanisms. In addition, brain cortical mitochondrial respiration and mtNOS activity and expression were analyzed as function of age. Mitochondrial NO production showed a decreasing tendency as a function of age. These results are in accordance with the protein expression analyzed by Western Blot of mitochondrial fractions which was 6.5 times higher in 1 month aged rats as compared with 14 old animals. Concomitant with these results, a clear increasing oxygen uptake tendency in state 3 respiration was observed, meanwhile only a slight increase was observed in state 4. All these results seems to be clearly related with the reversible and concentration-dependent attenuation of the respiratory chain by NO.

Aging↗

PubMed1987

Effects of vitamin D-induced chronic hypercalcemia on rat renal cortical plasma membranes and mitochondria.

Increases in intracellular and mitochondrial calcium content that accompany ischemic and toxic acute renal failure have been suggested to mediate renal tubular cell injury and dysfunction, but the mechanism(s) are unknown. We studied the effects of in vivo vitamin D-induced chronic hypercalcemia on rat renal cortical brush-border and basolateral membranes and mitochondria. In the brush-border membrane, hypercalcemia caused significant decreases in alkaline phosphatase-specific activity, total phospholipid molar content, and phosphatidylserine percent molar composition and increases in the cholesterol-to-total phospholipid molar ratio and phosphatidylinositol percent molar composition. In the basolateral membrane, hypercalcemia caused significant decreases in Na+-K+-ATPase-specific activity and total phospholipid molar content and increases in the cholesterol-to-total phospholipid molar ratio and phosphatidylinositol 4,5-bisphosphate percent molar composition. In the mitochondria, hypercalcemia caused a mild increase in the mitochondrial calcium content, but no alterations in succinic dehydrogenase-specific activity, succinate-, ADP-, or uncoupler-induced respiration. Thus hypercalcemia caused alterations in brush-border and basolateral membrane enzyme activity and lipid composition, but no functional changes were detected in mitochondria. These hypercalcemia-induced plasma membrane biochemical alterations may be markers of early cell injury and suggest a role for calcium in causing or predisposing to renal tubular cell injury.

Animals↗

PubMed2005

An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis.

Mitochondria play a central role in the life and death of cells. These organelles serve as the major energy-producing power-house, whereby the generation of ATP is associated with the utilization of molecular oxygen. A significant fraction (2-3%) of molecular oxygen consumed by mitochondria may be reduced in a one-electron fashion to yield a series of reactive oxygen species (ROS) such as superoxide anion radical, hydrogen peroxide, and hydroxyl radical. ROS are capable of damaging components of the electron transport apparatus and can, in turn, disrupt mitochondrial functioning, limiting cellular ATP levels and ultimately resulting in cell death. ROS-induced disruption of electron transport can perpetuate production of deleterious ROS and propagate mitochondrial damage. Consequently, mitochondria are highly enriched with water-soluble and lipid-soluble antioxidants (glutathione, ascorbate, Vitamin E, and coenzyme Q) and antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, catalase, thioredoxins, and peroxiredoxin. Another important antioxidant acting as a very effective scavenger of reactive lipid (peroxyl, alkoxyl) radicals is nitric oxide (NO) generated by mitochondrial nitric oxide synthase. However, NO can also be very disruptive to mitochondria function, a process facilitated by its high reactivity with superoxide. This interaction results in the formation of peroxynitrite, an oxidant capable of causing oxidative/nitrosative stress, further aggravating mitochondrial dysfunction, causing ATP depletion and damage to cells. Thus, in the most general sense, the effects of NO in mitochondria may be either protective or deleterious depending on specific conditions of local redox environment (redox potential, ratio of oxidized to reduced glutathione, transition metals, and the presence of other oxygen- and nitrogen-centered radicals).

Animals↗

PubMed2004

The molecular genetic basis of mitochondrial malfunction in bladder tissue following outlet obstruction.

PURPOSE: Bladder dysfunction following partial outlet obstruction is a frequent consequence of benign prostatic hyperplasia and an increasingly common problem given the aging of the general population. Recent studies from this and other groups have begun to elucidate the molecular bases for the well described physiological malfunctions that characterize this clinical entity. We summarized and synthesized that information. MATERIALS AND METHODS: Using modern methods of molecular genetics, including real-time polymerase chain reaction, real-time reverse transcriptase-polymerase chain reaction and others, as well as traditional experimental techniques such as electron microscopy we and others examined the transcriptional profile, morphology, etc of bladder smooth muscle mitochondria in experimental models of outlet obstruction. RESULTS: Data from many studies have demonstrated that aberrant gene expression in the mitochondrial and mitochondria related nuclear genetic systems underlies the loss of compliance and other attributes of bladder dysfunction following outlet obstruction. Such aberrant transcriptional characteristics engender loss of function in the electron transport and oxidative phosphorylation systems. Morphological studies of mitochondria in the animal model systems support this conclusion. CONCLUSIONS: In large part the loss of function in bladder smooth muscle following outlet obstruction results from the attenuation of mitochondrial energy production. In this article we reviewed and synthesized all available experimental observations relevant to this problem and we suggest future lines of inquiry that should prove fruitful in developing new strategies to treat the condition.

Animals↗

PubMed1999

Purine catabolism: links to mitochondrial respiration and antioxidant defenses?

Type I diabetes in rodents is associated with a spectrum of liver mitochondrial abnormalities ranging from evidence of oxidative stress and altered antioxidant defenses to frank defects in respiration rates and respiratory control ratios. To better address the myriad changes in redox metabolism in these mitochondria, we have applied new chromatographic techniques that enable simultaneous analysis of multiple components of pathways of interest (e.g., purine catabolites and oxidation by-products). We report here a portion of these results, which, in conjunction with other reported data, suggest that purine catabolism may contribute to mitochondrial antioxidant defenses by producing the antioxidant urate. In liver mitochondria from diabetic rats, increases in uric acid (threefold) and its direct precursor xanthine (sixfold) were observed in moderate diabetes, but levels fell essentially to normal in severe disease. Failure to maintain elevated xanthine and uric acid occurred contemporaneously with progressive mitochondrial dysfunction. Regression analysis revealed altered precursor-product relationships between xanthine, its precursors, and uric acid. An independent set of studies in isolated rat liver mitochondria showed that mitochondrial respiration was associated with essentially uniform decreases (approximately 30%) in all purine catabolites measured (urate, xanthine, hypoxanthine, guanine, guanosine, and xanthosine). That result suggests the potential for steady production of urate. Taken together, the two studies raise the possibility that purine catabolism may be a previously unappreciated component of the homeostatic response of mitochondria to oxidant stress and may play a critical role in slowing progressive mitochondrial dysfunction in certain disease states.

Animals↗

PubMed2002

Mitochondrial dysfunction and the role of the non-specialist laboratory.

Each human cell contains at least 1,000 mitochondria, each containing several copies of mitochondrial DNA. This DNA is tiny compared with the nuclear genome, and its structure and products have been fully elucidated. Whilst oxidative phosphorylation depends on the polypeptides encoded by mitochondrial DNA, it also requires a huge number of nuclear DNA products. Inherited deleterious mutations of mitochondrial DNA leading to inefficient oxidative phosphorylation have been described as 'mitochondrial disorders', with a variety of clinical presentations. When similar clinical presentations occur with no discernible mutation of mitochondrial DNA, histological and biochemical evidence is required for diagnosis. The number of these laboratory-proven inherited mitochondrial disorders is growing. It is also becoming clear that mitochondrial DNA defects can be acquired, the most common cause being therapy with highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1 (HIV-1) infection. Whilst definitive diagnosis of inherited or acquired mitochrondrial dysfunction requires access to specialist laboratory techniques, routine laboratories have a role to play in the initial investigation and monitoring of these conditions.

Cell Respiration↗