Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “mitochondrial dysfunction”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,549 records · Page 86Linked to original sources
PubMed1998

Role of mitochondrial Ca2+ regulation in neuronal and glial cell signalling.

It is becoming increasingly clear that mitochondrial Ca2+ uptake from and release into the cytosol has important consequences for neuronal and glial activity. Ca2+ regulates mitochondrial metabolism, and mitochondrial Ca2+ uptake and release modulate physiological and pathophysiological cytosolic responses. In glial cells, inositol 1,4,5-trisphosphate-dependent Ca2+ responses are faithfully translated into elevations in mitochondrial Ca2+ levels, which modifies cytosolic Ca2+ wave propagation and may activate mitochondrial enzymes. The location of mitochondria within neurones may partially determine their role in Ca2+ signalling. Neuronal death due to NMDA-evoked Ca2+ entry can be delayed by an inhibitor of the mitochondrial permeability transition pore, and mitochondrial dysfunction is being increasingly implicated in a number of neurodegenerative conditions. These findings are illustrative of an emerging realization by neuroscientists of the importance of mitochondrial Ca2+ regulation as a modulator of cellular energetics, endoplasmic reticulum Ca2+ release and neurotoxicity.

Animals↗
PubMed2000

Mitochondrial DNA-depleted neuroblastoma (Rho degrees) cells exhibit altered calcium signaling.

To investigate the role of chronic mitochondrial dysfunction on intracellular calcium signaling, we studied basal and stimulated cytosolic calcium levels in SH-SY5Y cells and a derived cell line devoid of mitochondrial DNA (Rho degrees ). Basal cytosolic calcium levels were slightly but significantly reduced in Rho degrees cells. The impact of chronic depletion of mitochondrial DNA was more evident following exposure of cells to carbachol, a calcium mobilizing agent. Calcium transients generated in Rho degrees cells following application of carbachol were more rapid than those in SH-SY5Y cells. A plateau phase of calcium recovery during calcium transients was present in SH-SY5Y cells but absent in Rho degrees cells. The rapid calcium transients in Rho degrees cells were due, in part, to increased reliance on Na(+)/Ca(2+) exchange activity at the plasma membrane and the plateau phase in calcium recovery in SH-SY5Y cells was dependent on the presence of extracellular calcium. We also examined whether mitochondrial DNA depletion influenced calcium responses to release of intracellular calcium stores. Rho degrees cells showed reduced responses to the uncoupler, FCCP, and the sarcoplasmic reticulum calcium ATPase inhibitor, thapsigargin. Acute exposure of SH-SY5Y cells to mitochondrial inhibitors did not mimic the results seen in Rho degrees cells. These results suggest that cytosolic calcium homeostasis in this neuron-like cell line is significantly altered as a consequence of chronic depletion of mitochondrial DNA.

Calcium↗
PubMed2004

Astrocyte mitochondria in in vitro models of ischemia.

There is growing evidence that preservation of mitochondrial respiratory function during cerebral ischemia-reperfusion predicts the ultimate extent of tissue injury. Because neurons are selectively vulnerable to ischemic injury, many studies have focused on neuronal mitochondrial dysfunction in ischemia. However, positron emission tomography (PET) studies in animals and humans suggest that non-neuronal cells such as astrocytes may also experience mitochondrial metabolic compromise that contributes to ischemic necrosis. Astrocytes carry out a number of functions that are critical to normal nervous system function, including uptake of neurotransmitters, regulation of pH and ion concentrations, and metabolic support of neurons. Mitochondria are important for many of these actions. We have used a cell culture model of stroke, oxygen-glucose deprivation (OGD), to study the response of astrocyte mitochondria to ischemia, and to evaluate how changes in astrocyte mitochondrial function might affect neuronal survival and recovery after ischemia.

Animals↗
PubMed2006

Mitochondrial fission is an upstream and required event for bax foci formation in response to nitric oxide in cortical neurons.

Mitochondrial dysfunction is an underpinning event in many neurodegenerative disorders. Less clear, however, is how mitochondria become injured during neuronal demise. Nitric oxide (NO) evokes rapid mitochondrial fission in cortical neurons. Interestingly, proapoptotic Bax relocates from the cytoplasm into large foci on mitochondrial scission sites in response to nitrosative stress. Antiapoptotic Bcl-xL does not prevent mitochondrial fission despite its ability to block Bax puncta formation on mitochondria and to mitigate neuronal cell death. Mitofusin 1 (Mfn1) or dominant-negative dynamin-related protein 1(K38A) (Drp1(k38A)) inhibits mitochondrial fission and Bax accumulation on mitochondria induced by exposure to an NO donor. Although NO is known to cause a bioenergetic crisis, lowering ATP by glycolytic or mitochondrial inhibitors neither induces mitochondrial fission nor Bax foci formation on mitochondria. Taken together, these data indicate that the mitochondrial fission machinery acts upstream of the Bcl-2 family of proteins in neurons challenged with nitrosative stress.

Adenosine Triphosphate↗
PubMed2004

Gene expression analysis in mitochondria from chagasic mice: alterations in specific metabolic pathways.

Cardiac hypertrophy and remodelling in chagasic disease might be associated with mitochondrial dysfunction. In the present study, we characterized the cardiac metabolic responses to Trypanosoma cruzi infection and progressive disease severity using a custom-designed mitoarray (mitochondrial function-related gene array). Mitoarrays consisting of known, well-characterized mitochondrial function-related cDNAs were hybridized with 32P-labelled cDNA probes generated from the myocardium of mice during immediate early, acute and chronic phases of infection and disease development. The mitoarray successfully identified novel aspects of the T. cruzi-induced alterations in the expression of the genes related to mitochondrial function and biogenesis that were further confirmed by real-time reverse transcriptase-PCRs. Of note is the up-regulation of transcripts essential for fatty acid metabolism associated with repression of the mRNAs for pyruvate dehydrogenase complex in infected hearts. We observed no statistically significant changes in mRNAs for the enzymes of tricarboxylic acid cycle. These results suggest that fatty acid metabolism compensates the pyruvate dehydrogenase complex deficiencies for the supply of acetyl-CoA for a tricarboxylic acid cycle, and chagasic hearts may not be limited in reduced energy (NADH and FADH2). The observation of a decrease in mRNA level for several subunits of the respiratory chain complexes by mitoarray as well as global genome analysis suggests a limitation in mitochondrial oxidative phosphorylation-mediated ATP-generation capacity as the probable basis for cardiac homoeostasis in chagasic disease.

Animals↗
PubMed2004

Mitochondrial respiratory deficiencies signal up-regulation of genes for heat shock proteins.

The consequences of mitochondrial dysfunction are not limited to the development of oxidative stress or initiation of apoptosis but can result in the establishment of stress tolerance. Using maize mitochondrial mutants, we show that permanent mitochondrial deficiencies trigger novel Ca(2+)-independent signaling pathways, leading to constitutive expression of genes for molecular chaperones, heat shock proteins (HSPs) of different classes. The signaling to activate hsp genes appears to originate from a reduced mitochondrial transmembrane potential. Upon depolarization of mitochondrial membranes in transient assays, gene induction for mitochondrial HSPs occurred more rapidly than that for cytosolic HSPs. We also demonstrate that in the nematode Caenorhabditis elegans transcription of hsp genes can be induced by RNA interference of nuclear respiratory genes. In both organisms, activation of hsp genes in response to mitochondrial impairment is distinct from their responses to heat shock and is not associated with oxidative stress. Thus, mitochondria-to-nucleus signaling to express a hsp gene network is apparently a widespread retrograde mechanism to facilitate cell defense and survival.

Animals↗
PubMed1991

Postischaemic reperfusion injury in the isolated rat heart: effect of ruthenium red.

STUDY OBJECTIVE: The aim was to investigate the effect of attenuating mitochondrial calcium uptake with ruthenium red on myocardial function and the resultant necrosis following prolonged ischaemia and reperfusion in isolated rat hearts. Mitochondrial dysfunction, secondary to increased calcium uptake, has been implicated as an important mediator of reperfusion injury in the heart. DESIGN: To examine the role of mitochondrial calcium uptake in mediating ischaemic and reperfusion injury, isolated rat hearts were perfused with ruthenium red (n = 6), a polysaccharide dye which inhibits calcium uptake by mitochondria, and were compared to control perfused hearts (n = 7). After stabilisation, hearts were subjected to 60 min no flow ischaemia, immediately followed by 40 min reperfusion. EXPERIMENTAL MATERIAL: Hearts were used from male Wistar rats weighing 300-350 g. MEASUREMENTS AND MAIN RESULTS: Cardiac high energy phosphates (ATP, phosphocreatine, inorganic phosphate) and pH were continuously monitored during ischaemia and reperfusion using phosphorus magnetic resonance spectroscopy. Contractility (dP/dT), coronary flow, creatine kinase release, and the time to the onset of ischaemic contracture were also measured. No differences in metabolic abnormalities or time to peak contraction during ischaemia were found between groups, suggesting that ruthenium red does not alter the metabolic consequences of ischaemia. However, upon reperfusion, the following differences in the ruthenium red perfused hearts were observed when compared to control hearts (p less than 0.05): ATP and phosphocreatine recovery were more complete, myocardial contractility was greater, coronary flow was greater, and myocyte necrosis was attenuated. CONCLUSIONS: Combined with the known inhibitory effect of ruthenium red on mitochondrial calcium uptake, these data suggest that an important component of myocardial injury following ischaemia and reperfusion in the isolated rat heart is the result of mitochondrial calcium accumulation.

Adenosine Triphosphate↗
PubMed2005

Zidovudine administration during pregnancy and mitochondrial disease in the offspring.

Prophylactic administration of zidovudine (ZDV) to mother-child pairs reduces HIV transmission. ZDV can impair mitochondrial (mt) DNA polymerase gamma, leading to mtDNA depletion. Signs of mitochondrial dysfunction have been observed in a few children with prenatal exposure to nucleoside analogues, although no mtDNA depletion was demonstrated. Other studies failed to confirm mitochondrial disorders in children who were exposed to antiretroviral agents in utero. A child, whose HIV-infected mother received ZDV from the fourth month of pregnancy, developed neonatal encephalomyopathy, anaemia and hyperlactataemia. At 2 weeks of age, a muscle biopsy exhibited red-ragged-like fibres, proliferation of abnormal mitochondria and a 90% depletion of mtDNA without qualitative abnormalities. At 6 months, the depletion was less profound (about 50% of normal values). Severe psychomotor delay and visual disturbances persisted at 30 months, but they were greatly reduced at 5-year follow-up. These laboratory and clinical findings clearly demonstrated that mtDNA alteration was acquired and not consequent to an inherited disorder. Fetal exposure to ZDV may have caused the mtDNA depletion, which, although temporary, led to irreversible but not progressive brain damage.

Anti-HIV Agents↗
PubMed1998

[Cerebral aging and mitochondria].

There are multiple evidences that corroborate the importance of mitochondrial dysfunction in the pathogenesis of cellular destruction that causes the aging, and that oxidative stress is the main inductor of these alterations. Damage of the mitochondrial DNA (deletions, duplications), defects of the respiratory chain function, and varied structural modifications have been described in humans and animals with the age. This mitochondrial damage, caused by the progressive action of oxidative stress, would influence in the mechanisms of maintenance of the cell, causing its death. We revised the most important discoveries regarding mitochondrial alterations with aging.

Aging↗
PubMed1992

Reactive oxygen and DNA damage in mitochondria.

During the last decade the importance of reactive oxygen species as major contributors to various types of cancer, heart diseases, cataracts, Parkinson's and other degenerative diseases that come with age, and to natural aging has become apparent. Mitochondria are the most important intracellular source of reactive oxygen. Mitochondrial DNA is heavily damaged by reactive oxygen at the bases, as indicated by the high steady-state level of 8-hydroxydeoxyguanosine, the presence of which causes mispairing and point mutations. Mitochondrial DNA is also oxidatively fragmented to a certain extent. Conceivably, such fragmentation relates to deletions found in mitochondrial DNA. Point mutations and deletions have recently been shown to be etiologically linked to several human diseases and natural aging. Future studies should address the causal relationship between mitochondrial dysfunction, production of reactive oxygen species, and aging.

Aging↗
PubMed1999

Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes.

Astrocytes protect neurons and oligodendrocytes by buffering ions, neurotransmitters, and providing metabolic support. However, astrocytes are also vulnerable to oxidative stress, which may affect their protective and supportive functions. This paper examines the influence of calcium and iron on astrocytes and determines if cell death could be mediated by mitochondrial dysfunction. We provide evidence that the events associated with peroxide-induced death of astrocytes involves generation of superoxide at the site of mitochondria, loss of mitochondrial membrane potential, and depletion of ATP. These events are iron-mediated, with iron loading exacerbating and iron chelation reducing oxidative stress. Iron chelation maintained the mitochondrial membrane potential, prevented peroxide-induced elevations in superoxide levels, and preserved ATP levels. Although increased intracellular calcium occurred after oxidative stress to astrocytes, the calcium increase was not necessary for collapse of mitochondrial membrane potential. Indeed, when astrocytes were oxidatively stressed in the absence of extracellular calcium, cell death was enhanced, mitochondrial membrane potential collapsed at an earlier time point, and superoxide levels increased. Additionally, our data do not support opening of the mitochondrial permeability transition pore as part of the mechanism of peroxide-induced oxidative stress of astrocytes. We conclude that the increase in intracellular calcium following peroxide exposure does not mediate astrocytic death and may even provide a protective function. Finally, the vulnerability of astrocytes and their mitochondria to oxidative stress correlates more closely with iron availability than with increased intracellular calcium.

Adenosine Triphosphate↗
PubMedDate not supplied

Biochemical relationships between Reye's and Reye's-like metabolic and toxicological syndromes.

Reye's syndrome is a hepatic encephalopathy with fatty infiltration of the liver and is due to mitochondrial dysfunction. Knowledge of the mechanisms causing Reye's syndrome has been gained from the study of Reye's syndrome-like diseases, including inborn errors of mitochondrial energy production, viral disease and toxicological injury. Entry of fatty acids into mitochondria or beta-oxidation itself may be impaired. Toxins such as hypoglycin, pentanoate, valproate, salicylate, and their metabolites inhibit beta-oxidation pathways and can produce Reye's syndrome-like presentations. Biochemical manifestations of the diverse causes of Reye's syndrome-like disorders are similar and include: hypoglycaemia due to impaired gluconeogenesis, accumulation of fatty acids, fatty acyl CoAs, and acyl carnitines with depletion of free CoA and carnitine. Accumulated products may further injure mitochondria and exacerbate impaired beta-oxidation, uncouple oxidative phosphorylation or increase mitochondrial permeability. Mitochondrial swelling and steatosis of hepatic cells are the histological result. With the advances of biochemical techniques for the study of organic acid excretion patterns, serum fatty acid patterns and identification of enzymatic deficiencies in cells from patients with Reye's syndrome-like presentations, it is clear that Reye's syndrome is, in part, a collection of various inborn errors and toxicological states. Circumstances such as viral disease, prolonged fasting and drugs may precipitate clinical expression of these deficiencies as Reye's syndrome. As work progresses, further causes of Reye's syndrome will be identified.

Animals↗
PubMed2006

Dysregulation of mitochondrial fusion and fission: an emerging concept in neurodegeneration.

Mitochondrial dysfunction is increasingly being recognized as an important factor contributing to the pathogenesis of neurodegenerative disorders. However, at present, the molecular basis underlying the decline in mitochondrial function is not really understood, but recent experimental evidence has shed some light on the pivotal role of mitochondrial morphology control in this process. In particular, dysregulated mitochondrial fusion and fission events can now be regarded as playing important pathogenic roles in neurodegeneration. In healthy cells, mitochondrial morphology is maintained through a dynamic balance between fusion and fission processes, and this regulated balance seems to be required for maintaining normal mitochondrial and cellular function. Moreover, during programmed cell death, activation of mitochondrial fission occurs, leading to mitochondrial fragmentation (Karbowski et al. in J Cell Biol 164:493-499, 2004). Consequently, inhibition of mitochondrial fission results in a significantly reduced cellular susceptibility toward apoptosis. The clinical relevance of maintaining a finely tuned balance between mitochondrial fusion and fission processes is underscored by the fact that the pathogenesis of certain hereditary neurodegenerative disorders such as autosomal dominant optic atrophy (ADOA) and Charcot-Marie-Tooth neuropathy type 2A (CMT2A) can now be linked to mutations in genes encoding mediators of mitochondrial fusion. In this article, I will summarize important aspects of what is currently known about the molecular machinery regulating mitochondrial fission and fusion in mammalian cells. Special emphasis will be given to the consequences of dysregulated mitochondrial morphology with regard to the pathogenesis of neurodegenerative disorders. A detailed understanding of the mitochondrial fission and fusion machinery will be a prerequisite for the development of therapeutic approaches to inhibit the neuronal cell death underlying certain neurodegenerative disorders.

Animals↗
PubMed2005

Maternal lineages and Alzheimer disease risk in the Old Order Amish.

Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%) while observed in only 10.6% in outbred American and European populations. Furthermore, haplogroups J and K are less frequent (1.0%) than in the outbred data set (9.4-11.2%). Affected case matrilines and unaffected control lines were chosen from pedigrees to test whether specific haplogroups and their defining SNPs confer risk of AD. We did not observe frequency differences between AD cases compared to controls overall or when stratified by sex. Therefore, we suggest that the genetic effect responsible for AD dementia in the affected Amish pedigrees is unlikely to be of mitochondrial origin and may be caused by nuclear genetic factors.

Alzheimer Disease↗
PubMed1995

Biochemical studies of isolated mitochondria from normal and diseased tissues.

Isolated mitochondria have served as useful tools for identifying the site(s) of impairment associated with respiratory chain-linked oxidative phosphorylation at the molecular level. Over the last three decades, a number of diseases associated with mitochondrial dysfunction have been identified. The literature is large and diverse. This paper presents a brief survey of the current state of knowledge concerning biochemical studies of mitochondrial diseases associated with skeletal muscle, such as mitochondrial myopathies and, with brain injury such as that induced by ischemia/reperfusion. Various mitochondrial preparations and assay conditions are evaluated. The importance of fresh tissue for the isolation of tightly coupled mitochondria and the selection of suitable assay conditions for characterization have been demonstrated. Appropriate methodologies for isolation and characterization of tightly coupled mitochondria from both skeletal muscle and brain are presented.

Animals↗
PubMed2005

Role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury in rat hepatocytes.

The role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury was studied in mitochondria and hepatocytes isolated from rat liver. Mitochondrial permeability transition has been proposed as a common final pathway in acute cell death through mitochondrial dysfunction. In isolated mitochondria, N-nitrosofenfluramine (0.25 to 1.0 mM) in the presence of Ca(2+) (50 microM) elicited a concentration-dependent induction of mitochondrial swelling dependent on mitochondrial permeability transition and the release of cytochrome c, both of which were prevented by pretreatment with a specific inhibitor of mitochondrial permeability transition, cyclosporin A (0.2 microM). The effects of N-nitrosofenfluramine on mitochondria were more potent than those of fenfluramine, which is a sympathomimetic amine with anorectic action. The pretreatment of isolated hepatocytes with cyclosporin A (2 microM) partially but not completely prevented N-nitrosofenfluramine (0.6 mM; a low toxic dose)-induced cell death, loss of cellular ATP, formation of cell blebs and decrease in mitochondrial membrane potential. These results suggest that the onset of N-nitrosofenfluramine-induced cytotoxicity is linked to mitochondrial failure dependent upon induction of mitochondrial permeability transition accompanied by mitochondrial depolarization, the release of cytochrome c and depletion of intracellular ATP through uncoupling of oxidative phosphorylation.

Animals↗
PubMed1983

Anti-tumour cytotoxin produced by human monocytes: studies on its mode of action.

Human monocytes can be induced to synthesize a cytotoxin which affects certain tumour cell lines. The interaction of monocyte cytotoxin with a susceptible cell line (L929) has been studied to obtain clues to the mode of action of the cytotoxin. The cytotoxin acts directly on the cells rather than on the culture medium and is cytotoxic at higher concentrations and cytostatic at lower concentrations. First signs of cell damage appear about 20 h after contact with the cytotoxin which must be present throughout this period. The cytotoxin probably acts on the cell surface and is more effective at 40 degrees C than at 37 degrees C. For a given amount of cytotoxin the effects are inversely proportional to the target cell concentration. Treatment of the cytotoxin with phenanthroline inhibits cytotoxicity while treatment of the target cells with actinomycin D, but not cycloheximide or puromycin, enhances cytotoxicity. After 24 h cytotoxin treatment the target cells exhibit reduced respiration rate but enhanced glycolysis and glucose uptake suggesting mitochondrial dysfunction. A possible interpretation of these data is that the monocyte cytotoxin is a metalloenzyme which inactivates a cell surface receptor for a nutrient essential for mitochondrial function.

Adsorption↗
PubMed2003

MitoDrome: a database of Drosophila melanogaster nuclear genes encoding proteins targeted to the mitochondrion.

Mitochondria are organelles present in the cytoplasm of most eukaryotic cells; although they have their own DNA, the majority of the proteins necessary for a functional mitochondrion are coded by the nuclear DNA and only after transcription and translation they are imported in the mitochondrion as proteins. The primary role of the mitochondrion is electron transport and oxidative phosphorylation. Although it has been studied for a long time, the interest of researchers in mitochondria is still alive thanks to the discovery of mitochondrial role in apoptosis, aging and cancer. Aim of the MitoDrome database is to annotate the Drosophila melanogaster nuclear genes coding for mitochondrial proteins in order to contribute to the functional characterization of nuclear genes coding for mitochondrial proteins and to knowledge of gene diseases related to mitochondrial dysfunctions. Indeed D. melanogaster is one of the most studied organisms and a model for the Human genome. Data are derived from the comparison of Human mitochondrial proteins versus the Drosophila genome, ESTs and cDNA sequence data available in the FlyBase database. Links from the MitoDrome entries to the related homologous entries available in MitoNuC will be soon imple-mented. The MitoDrome database is available at http://bighost.area.ba.cnr.it/BIG/MitoDrome. Data are organised in a flat-file format and can be retrieved using the SRS system.

Animals↗