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PubMed1993

Enteroviruses and postviral fatigue syndrome.

Postviral fatigue syndrome (PFS) occurs both in epidemics and sporadically. Many of the original epidemics were related to poliomyelitis outbreaks which either preceded or followed them. The core clinical symptoms are always the same: severe fatigue made worse by exercise, myalgia, night sweats, atypical depression and excessive sleep. The other common symptoms include dysequilibrium disorders and irritable bowel syndrome. We have detected enteroviral genome sequences in muscle biopsies from cases of PFS, using specific enteroviral oligonucleotide primers in the polymerase chain reaction (PCR). In addition, whole virus particles can be demonstrated in PCR-positive muscle, using solid-phase immuno-electron microscopy. An increase in the number and size of muscle mitochondria was found in 70% of PFS cases, suggesting an abnormality in metabolic function. Evidence of hypothalamic dysfunction was present, particularly involving 5-hydroxytryptamine metabolism. A putative model of PFS, based on persistent enteroviral infection in laboratory mice, revealed resolving inflammatory lesions in muscle with, however, a marked increase in the production of certain cytokines in the brain. This model may help to explain the pathogenesis of PFS.

Animals↗

PubMed1991

Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A.

Cyclosporin A is a potent immunosuppressant used to prevent graft rejection. The cellular target of cyclosporin A in T lymphocytes is believed to be cyclophilin, a ubiquitous protein with peptidyl prolyl cis trans isomerase activity located in both the cytosol and mitochondria. Recently, cyclosporin A-inhibition of mitochondrial cyclophilin has been implicated in the prevention of mitochondrial dysfunction induced in vitro by Ca2+ overload and other factors potentially relevant to ischaemic cell injury. This study investigates the effect of cyclosporin A on injury to cardiomyocytes induced by substrate-free anoxia. It is shown that cyclosporin A retards progression of the injury, most probably at a late step in the injury process.

Animals↗

PubMed2004

Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid.

5-Aminolevulinic acid (ALA) is a heme precursor accumulated in plasma and in organs in acute intermittent porphyria (AIP), a disease associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma (HCC). Liver biopsies of AIP patients showed odd-shaped mitochondria and autophagic vacuoles containing well-preserved mitochondria. ALA yields reactive oxygen species upon metal-catalyzed oxidation and causes in vivo and in vitro impairment of rat liver mitochondria and DNA damage. Using a quantitative polymerase chain reaction assay, we demonstrated that ALA induces a dose-dependent damage in nuclear and mitochondrial DNA in human SVNF fibroblasts and rat PC12 cells. CHO cells treated with ALA also show nuclear DNA damage and human HepG2 cells entered in apoptosis and necrosis induced by ALA and its dimerization product, DHPY. The present data provide additional information on the genotoxicity of ALA, reinforcing the hypothesis that it may be involved in the development of HCC in AIP patients.

Aminolevulinic Acid↗

PubMed1998

Molecular genetics and pathogenesis of Friedreich ataxia.

Friedreich ataxia, the most frequent cause of inherited ataxia, is due in most cases to 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 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↗

PubMed2003

Mitochondrial disruption and apoptosis in lymphocytes of an HIV infected patient affected by lactic acidosis after treatment with highly active antiretroviral therapy.

AIMS: Highly active antiretroviral therapy (HAART) can induce an increase in lactic acid concentrations that seems to be caused by mitochondrial dysfunction induced by the interaction of nucleoside reverse transcriptase inhibitors (NRTIs) with DNA polymerase gamma in the mitochondria. Mitochondrial alterations have been described in liver and muscle cells of NRTI treated human immunodeficiency virus (HIV) infected patients. Because lymphocytes are the main target for HIV and because mitochondria are involved in apoptosis, we studied mitochondrial morphology and apoptosis in the lymphocytes of an HIV infected patient with severe lactic acidosis after treatment with stavudine, didanosine, and indinavir. METHODS: The patient was a 39 year old woman. After two years of treatment she developed rapid weight loss with severe fat wasting, peripheral neuropathy, and hyperlacticaemia, which persisted after treatment withdrawal. The numbers and the morphology of the mitochondria were evaluated by electronic microscopy; the percentage of apoptotic cells was calculated by flow cytometry after staining with annexine V and by fluorescent microscopy after staining with ethidium bromide and acridine orange. RESULTS: The numbers of mitochondria in the lymphocytes were greatly decreased when compared with the lymphocytes of healthy individuals. The most important mitochondrial morphological alterations were swelling and the disruption of cristae and internal mitochondrial structure. These alterations were more evident during the period in which lactic acid values were very high. Moreover, a high percentage of apoptotic lymphocytes was seen. Morphological examination conducted one week after the normalisation of lacticaemia showed a pronounced increase in the number of mitochondria. The morphological alterations were no longer evident, although the size of each mitochondrion was smaller than normal. Moreover, the percentage of apoptotic cells was lower than 5%. CONCLUSIONS: This report describes important morphological alterations in lymphocyte mitochondria in an HIV infected patient during a severe phase of HAART induced hyperlacticaemia. These alterations persisted for several weeks after treatment withdrawal and were associated with an increase in lymphocyte apoptosis. Considering the important role of mitochondria in the apoptotic pathway, the increase in lymphocyte apoptosis may be a consequence of proapoptotic factors released from altered mitochondria.

Acidosis, Lactic↗

PubMed2005

The role of apoptosis in age-related skeletal muscle atrophy.

Skeletal myocyte atrophy and death contribute to sarcopenia, a condition associated with normal aging. By 80 years of age, it is estimated that humans generally lose 30-40% of skeletal muscle fibres. The mechanism for this loss is unknown; however, it may involve apoptosis. Mitochondrial dysfunction and sarcoplasmic reticulum (SR) stress that occurs with age may be possible stimuli inducing apoptosis. Hence, mitochondria and SR may be important organelles within skeletal myocytes responsible for apoptosis signalling. The activation of apoptosis may be partly responsible for the initiation of muscle protein degradation, loss of muscle nuclei associated with local atrophy, and cell death of the myocyte. Exercise training and caloric restriction are two interventions known to enhance skeletal muscle function. The effects of these interventions on apoptosis are discussed.

Aging↗

PubMed2006

N-terminal segments are the functional domains of CLN3-encoded battenin for protein interactions.

OBJECTIVE: Batten disease (BD), the juvenile form of neuronal ceroid lipofuscinosis (NCLs), is pathological characterized by finding lysosomal storage of autofluorescent lipofuscins with unique ultrastructural profiles. The gene underlying BD is designated CLN3 and encodes a protein, Battenin, of unknown function that localizes in lysosomes and/or mitochondria. Previously, we hypothesized that Battenin associates with other membrane protein(s) to form a membrane complex. Dysfunction of this complex could result in the pathological changes of BD, and possibly in other NCLs. Two such membranous proteins, the slow and fast Battenin-interactive proteins (BIPs and BIPf) of unknown functions, have been identified. In this study, we have characterized the functional domains of Battenin that interact with both BIP proteins. METHODS: Protein-protein interactions with a yeast two-hybrid system were employed. A "deletion assay" was employed to localize the interactive segment(s). Different lengths of cDNA sequences lacking exon 1-5 were used to express CLN3-encoded proteins lacking N-terminal segments in the yeast two-hybrid system. N-terminal exons of CLN3 were deleted with PCR-cloning strategies. RESULTS: We eliminated the possibility of interacting domains from the exon 7-encoded region because both Battenin and mBattenin interact with the BIP proteins. We have shown that peptide sequences encoded by exons 2 and 4 of CLN3 gene include the functional domains by which Battenin interacts with the BIP proteins. CONCLUSION: Our studies provide evidence that the N-terminus of Battenin is the functional domain for these protein interactions.

DNA, Complementary↗

PubMed2004

Degraded cardiomyocytes and dysfunctional energy metabolism; their relationship with canine cardiomyopathies.

Tissue sections from hearts of dogs suffering from cardiomyopathies were studied histologically and ultrastructurally. Two types of mitochondrial changes were defined and quantitated. Mitochondrial hypertrophy occurred in cardiomyocytes of middle-aged and older dogs. Significant numbers of degraded cardiomyocytes related to hydropic degeneration of hypertrophied mitochondria associated with autolysis of contractile elements and loss of cellular physiochemical functions were seen in hearts of old dogs with cardiomyopathy. Dogs with cardiac disease that were treated to enhance dysfunctional energy production early in the course of disease had cellular changes similar to those seen in old dogs but they survived heart disease and ultimately died of other causes.

Journal Article↗

PubMed2005

Interventions with neuroprotective agents: novel targets and opportunities.

Several antiepileptic drugs have demonstrated neuroprotective properties in animal models by inhibiting the components of the excitotoxic cascade. The process of neurodegeneration appears to be dependent on the mitochondria, with their central role as regulators of both energy metabolism and apoptotic pathways during seizures. Excess cytosolic Ca(2+) during periods of excitotoxicity disrupts homeostasis in the mitochondria, causing inhibition of adenosine triphosphate synthesis and increased production of reactive oxygen species, with resultant oxidative damage, leading to neuronal cell death. The Ca(2+)-mediated mitochondrial dysfunction in epilepsy may be the main target for neuroprotective intervention by antiepileptic drugs.

Animals↗

PubMed1989

Biochemical and morphological changes in myocardium during coronary occlusion and reperfusion in canine hearts: effects of propranolol on myocardial damage.

To clarify the mechanism of irreversible myocardial damage, we studied the relationship between ischaemic mitochondrial dysfunction and leakage of lysosomal enzymes, and the effects of propranolol on myocardial damage. Open chest anaesthetised dogs were divided into six groups: 30 min occlusion of the left anterior coronary artery (LAD); 2 h LAD occlusion; 2 h LAD occlusion after premedication with 0.3 mg.kg-1 propranolol; 30 min LAD occlusion/l h reperfusion; 2 h LAD occlusion/l h reperfusion; and 2 h LAD occlusion/l h reperfusion after propranolol premedication. After occlusion or reperfusion, heart mitochondria were prepared from normal and occluded or reperfused areas, and mitochondrial function (rate of oxygen consumption in State III, and respiratory control index) was measured polarographically. Myocardial tissue was fractionated and activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase and beta-glucuronidase) were measured. Electron microscopic studies were performed. Thirty min occlusion induced mitochondrial dysfunction without leakage of lysosomal enzymes. Reperfusion for 1 h reversed these changes. However occlusion for 2 h induced mitochondrial dysfunction associated with the leakage of lysosomal enzymes, and mitochondrial dysfunction was not reversed by 1 h reperfusion. Propranolol reduced mitochondrial dysfunction after 2 h occlusion and prevented leakage of lysosomal enzymes. Mitochondrial function was fairly well maintained after 1 h reperfusion in dogs premedicated with propranolol. Structural changes in mitochondria were observed in the 2 h occlusion/l h reperfusion group, and were reduced by premedication with propranolol. These results suggest that irreversible injury of ischaemic mitochondria is closely linked with instability of lysosomal membranes, and that propranolol prevented irreversible myocardial mitochondrial dysfunction.

Animals↗

PubMed2004

Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover.

Inhibition of proteasome activity occurs in normal aging and in a wide variety of neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. Although each of these conditions is also associated with mitochondrial dysfunction potentially mediated by proteasome inhibition, the relationship between proteasome inhibition and the loss of mitochondrial homeostasis in each of these conditions has not been fully elucidated. In this study, we conducted experimentation in order to begin to develop a more complete understanding of the effects proteasome inhibition has on neural mitochondrial homeostasis. Mitochondria within neural SH-SY5Y cells exposed to low level proteasome inhibition possessed similar morphological features and similar rates of electron transport chain activity under basal conditions as compared with untreated neural cultures of equal passage number. Despite such similarities, maximal complex I and complex II activities were dramatically reduced in neural cells subject to proteasome inhibition. Proteasome inhibition also increased mitochondrial reactive oxygen species production, reduced intramitochondrial protein translation, and increased cellular dependence on glycolysis. Finally, whereas proteasome inhibition generated cells that consistently possessed mitochondria located in close proximity to lysosomes with mitochondria present in the cellular debris located within autophagosomes, increased levels of lipofuscin suggest that impairments in mitochondrial turnover may occur following proteasome inhibition. Taken together, these data demonstrate that proteasome inhibition dramatically alters specific aspects of neural mitochondrial homeostasis and alters lysosomal-mediated degradation of mitochondria with both of these alterations potentially contributing to aging and age-related disease in the nervous system.

Animals↗

PubMed2006

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia.

SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to alpha-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoietic failure, and elevated alpha-ketoglutarate in the amniotic fluid. We found that these animals have normal mitochondrial ribo- and deoxyribonucleoside triphosphate levels, suggesting that transport of these molecules is not the primary role of SLC25A19. We identified thiamine pyrophosphate (ThPP) transport as a candidate function of SLC25A19 through homology searching and confirmed it by using transport assays of the recombinant reconstituted protein. The mitochondria of Slc25a19(-/-) and MCPHA cells have undetectable and markedly reduced ThPP content, respectively. The reduction of ThPP levels causes dysfunction of the alpha-ketoglutarate dehydrogenase complex, which explains the high levels of this organic acid in MCPHA and suggests that mitochondrial ThPP transport is important for CNS development.

Anemia↗

PubMed2005

Adaptive responses to mitochondrial dysfunction in the rho degrees Namalwa cell.

Mitochondrial function depends on the synchronised expression of nuclear and mitochondrial-encoded genes. The expression of many nuclear genes is sensitive to the functional state of mitochondria. Mitochondria containing mutated mtDNA populations have been shown to withstand stress to a high level of tolerance. The prolonged survival of cells that are devoid of mitochondrial DNA is further evidence for the existence of this adaptive response. Yeast cells lacking the mitochondrial genome configure their pattern of nuclear gene expression to accommodate changes in nutrient availability and in response to different stress conditions. Little is known about the signalling pathways that mediate the adaptive response in mammalian cells with mitochondrial dysfunction. To gain a global perspective on adaptive responses in cells with mitochondrial dysfunction, we used Affymetrix microarray technology to compare the whole genome transcription profile of Namalwa cells (rho(+)) to that of a Namalwa cell depleted of mitochondrial DNA (rho degrees ). Our results demonstrate that rho degrees Namalwa induce genes encoding hypoxia target proteins, mitochondrial ribosomal proteins, transport channels, tRNA synthetases and enzymes of the glycolytic pathway and the fatty oxidation pathway suggesting that hypoxia and the ensuing cellular adaptations could play an important adaptive role in cells with mitochondrial dysfunction.

Adaptation, Physiological↗

PubMed1991

Mitochondrial abnormalities in human sural nerves: fine structural evaluation of cases with mitochondrial myopathy, hereditary and non-hereditary neuropathies, and review of the literature.

Fifteen cases of mitochondrial myopathy, three cases of hereditary motor and sensory neuropathy (HMSN) VI, and 280 cases of neuropathies of different etiologies were examined by electron microscopy for the presence of mitochondrial abnormalities in the sural nerve. Altered mitochondrial were found in most cases of mitochondrial myopathy, in all cases of HMSN VI, and in 25 cases out of the series of unselected neuropathies. The mitochondrial changes comprised enlargement with an amorphous matrix and distorted cristae, with hexagonal paracrystalline inclusions, and with prominent cristae containing oblique striations, and a variety of rare changes. Most mitochondrial abnormalities were found in Schwann cells. An increase of the number of mitochondria was noted in smooth muscle and endothelial cells of epineurial arterioles of two cases with mitochondrial encephalomyopathy. Neuropathy was present in all cases of mitochondrial myopathy according to morphometrical analysis. Whether neuropathy is caused directly by mitochondrial dysfunction or by other pathogenetic mechanisms remains to be determined.

Hereditary Sensory and Autonomic Neuropathies↗

PubMedDate not supplied

Asbestos-induced alveolar epithelial cell apoptosis: role of mitochondrial dysfunction caused by iron-derived free radicals.

Asbestos causes asbestosis and malignancies by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) injury by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. We previously showed that iron-catalyzed ROS in part mediate asbestos-inducedAEC DNA damage and apoptosis. Mitochondria have a critical role in regulating apoptosis after exposure to agents causing DNA damage but their role in regulating asbestos-induced apoptosis is unknown. To determine whether asbestos causes AEC mitochondrial dysfunction, we exposed A549 cells to amosite asbestos and assessed mitochondrial membrane potential changes (delta(psi)m) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. We show that amosite asbestos, but not an inert particulate, titanium dioxide, reduces delta(psi)m after a 4 h exposure period. Further, the delta(psi)m after 4 h was inversely proportional to the levels of apoptosis noted at 24 h as assessed by nuclear morphology as well as by DNA nucleosome formation. A role for iron-derived ROS was suggested by the finding that phytic acid, an iron chelator, blocked asbestos-induced reductions in A549 cell delta(psi)m and attenuated apoptosis. Finally, overexpression of Bcl-xl, an anti-apoptotic protein that localizes to the mitochondria, prevented asbestos-induced decreases in A549 cell delta(psi)m after 4 h and diminished apoptosis. We conclude that asbestos alters AEC mitochondrial function in part by generating iron-derived ROS, which in turn can result in apoptosis. This suggests that the mitochondrial death pathway is important in regulating pulmonary toxicity from asbestos.

Apoptosis↗

PubMed2005

Okadaic acid induces JNK activation, bim overexpression and mitochondrial dysfunction in cultured rat cortical neurons.

Apoptosis via tau phosphorylation has been implicated in the selective neuronal losses seen in Alzheimer's disease (AD). Previous studies in vivo and in cultured neurons have shown that okadaic acid (OA) evokes tau phosphorylation to initiate a neurodegeneration that resembles the pathogenesis of AD. In an effort to identify additional key molecules in this neurodegeneration, we treated cultured rat neurons with OA and examined the apoptosis-related effects, such as changes in mitochondrial activity and expression levels of JNK, Bim, Bad, Bax and caspase-3. Western blotting revealed that phosphorylation of JNK and c-jun occurred first, followed by increased expression of Bim and subsequent caspase-3 activation in OA-treated neurons. In contrast, Bad levels decreased as early as 4 h after OA treatment. Immunocytochemistry showed that the increased phospho-JNK immunoreactivity was localized in the cytosol of degenerating neurons, while increased phospho-c-jun was localized in the nucleus. The mitochondria showed decreased membrane potential and increased swelling after OA treatment. Collectively, these data suggest that JNK- and Bim-related mitochondrial dysfunction is involved in OA-induced neurodegeneration.

Animals↗

PubMed2005

Endurance training limits the functional alterations of rat heart mitochondria submitted to in vitro anoxia-reoxygenation.

BACKGROUND: Studies analysing the effect of endurance training on heart mitochondrial function submitted to in vitro anoxia-reoxygenation (A-R) are missing. The present study aimed to investigate the effect of moderate endurance treadmill training (14 weeks) against rat heart mitochondrial dysfunction induced by in vitro A-R. METHODS: Respiratory parameters (state 3, state 4, ADP/O and respiratory control ratio-RCR) and oxidative damage markers (carbonyl groups and malondialdehyde) were determined in isolated mitochondria before and after 1 min anoxia followed by 4 min reoxygenation. Levels of heat shock protein 60 kDa (HSP60) and 70 kDa (HSP70) were measured before A-R in mitochondria and whole muscle homogenate, respectively. RESULTS: A-R significantly impaired the rate of state 3 and state 4 respiration, as well as the RCR and ADP/O in the sedentary group. However, mitochondrial state 3 respiration was significantly higher in trained than in the sedentary group both before and after A-R. The impairments in RCR, ADP/O ratio and state 4 induced by A-R in sedentary group were significantly attenuated in endurance-trained group. The inhibition of state 4 induced by GDP was significantly higher in trained than in sedentary group. Oxidative modifications of mitochondrial proteins and phospholipids were found in sedentary group after A-R, although limited in trained group. Increased levels of mitochondrial HSP60 and tissue HSP70 accompanied the lower decrease in the respiratory function after A-R observed in trained group. CONCLUSION: We therefore concluded that endurance training limited the impairments on rat heart mitochondria caused by the oxidant insult inflicted by in vitro A-R.

Animals↗

PubMed1999

Protective effect of Phyllanthus fraternus against carbon tetrachloride-induced mitochondrial dysfunction.

The effect of carbon tetrachloride administration on liver mitochondrial function and the protective effect of an aqueous extract of Phyllanthus fraternus were studied in rats. The following changes were observed in mitochondria due to the administration of carbon tetrachloride. 1) A decrease in the rate of respiration, respiratory control ratio and P/O ratio using glutamate and malate or succinate as substrates. 2) A decrease in the activities of NADH dehydrogenase (35%), succinate dehydrogenase (76%) and cytochrome c oxidase (51%). The rate of electron transfer through site I, site II and site III was studied independently and found to be significantly decreased. 3) A decrease in the content of cytochrome aa3 (34%). 4) A significant decrease in the levels of phospholipids particularly cardiolipin and a significant increase in the lipid peroxide level was observed. The carbon tetrachloride induced toxicity may be partly due to the lipid peroxidation and partly due to the effect on protein synthesis. Administration of rats with an aqueous extract of P. fraternus prior to carbon tetrachloride administration showed significant protection on the carbon tetrachloride induced mitochondrial dysfunction on all the parameters studied.

Alanine Transaminase↗