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Results for “mitochondrial dysfunction”

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PubMed1996

Relationship between mitochondrial dysfunction and toxicity of propyl gallate in isolated rat hepatocytes.

The relationship between cytotoxicity and mitochondrial dysfunction caused by propyl gallate (PG) has been studied in hepatocytes freshly prepared from fasted rats. Hepatocytes isolated from fasted (18 h) rats were significantly more susceptible to the toxicity of PG than hepatocytes from fed rats. The addition of fructose (15 mM), an alternative carbohydrate source, to hepatocyte suspensions resulted in the prevention of PG (1 mM)-induced cell killing accompanied by decrease in intracellular ATP loss during a 3 h-incubation period. Despite this, fructose did not completely prevent an abrupt loss of intracellular glutathione caused by PG, but effectively inhibited the loss of protein thiol levels. Fructose elicited a concentration (0.5-20mM)-dependent protection against the cytotoxicity of 1.5 mM PG. The incubation of hepatocytes with sodium azide (4 mM), an inhibitor of oxidative phosphorylation, enhanced the toxicity induced by PG (1 mM), but coincubation with fructose delayed the onset of toxicity. Neither azide alone nor fructose plus azide did affect the cell viability during the incubation period. Furthermore, the addition of 2 mM salicylamide, nontoxic to hepatocytes during the incubation period, enhanced PG (1 mM)-induced cytotoxicity and decreased the loss of free PG. These results indicate that the onset of cytotoxicity caused by PG may depend on the intracellular energy status and that mitochondria are critical target for the compound. In addition, the toxicity caused by the inhibition of mitochondrial ATP synthesis is related to the concentration of PG remaining in cell suspensions.

Adenosine Triphosphate↗

PubMed1978

The effect of mitochondrial dysfunction on glucose metabolism during shock.

Hepatic glycogen content, blood glucose and lactate concentrations, and hepatic mitochondrial energy-linked functions were measured in rats in late hemorrhagic shock. As judged by correlation coefficients, the following significant relationships were noted: (formula: see text). Glycogen depletion, hypoglycemia, and lactic acidemia occurred frequently. However, alone or in combination, these variables did not relate significantly to need for or amount of shed blood uptake prior to sacrifice. Neither hepatic glycogen depletion nor uncoupled hepatic mitochondrial oxidative phosphorylation alone accounted for hypoglycemia. The genesis of hypoglycemia was determined by the occurrence of both these events in either sequence. When hepatic mitochondrial oxidative phosphorylation became uncoupled, the blood glucose concentration and hepatic glycogen content were linearly related (r = 0.94). This effect probably results from impaired gluconeogenesis due to mitochondrial dysfunction.

Animals↗

PubMed2000

Morphological correlates of mitochondrial dysfunction in children.

Morphological studies have traditionally played a major role in the study of adults with suspected mitochondrial diseases. Here we review their role in the investigation of paediatric patients. The morphological changes may be macroscopic, such as developmental abnormalities of the brain in pyruvate dehydrogenase deficiency, including ectopic inferior olives and the absence of corpus callosum and pyramids. Other changes are histological, such as rarefaction of the neuropil and endothelial prominence in Leigh syndrome, and spongiosis with neuronal loss and gliosis in Alpers disease. The ragged-red fibres typical of mitochondrial disease in adults are only rarely seen in skeletal muscle biopsies from children. On the other hand, dramatic ultrastructural changes involving the mitochondria may be seen in many organs, including the liver, heart and intestine. In Alpers and lethal infantile mitochondrial diseases, the hepatocytes show marked accumulation of small droplets of lipid alternating with densely packed mitochondria with pale matrix and loss of granules. These changes are associated with a marked decrease in respiratory chain enzyme activity in the liver, often without similar decrease in the skeletal muscle or fibroblasts. Enlarged mitochondria with concentric cristae are prominent in the cardiac myocytes in Barth syndrome. For the assessment of children with a suspected disorder of mitochondrial dysfunction, detailed morphological studies of the brain (at autopsy) and of biopsies (especially of the liver), including ultrastructural assessment of the mitochondria, can be a very useful preliminary investigation. The findings should then be correlated with the clinical features and used as a guide for further biochemical and molecular studies, preferably on multiple tissues.

Adolescent↗

PubMed2001

Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria.

Extensive complementation between fused mitochondria is indicated by recombination of 'parental' mitochondrial (mt) DNA (ref. 1,2) of yeast and plant cells. It has been difficult, however, to demonstrate the occurrence of complementation between fused mitochondria in mammalian species through the presence of recombinant mtDNA molecules, because sequence of mtDNA throughout an individual tends to be uniform owing to its strictly maternal inheritance. We isolated two types of respiration-deficient cell lines, with pathogenic mutations in mitochondrial tRNAIle or tRNALeu(UUR) genes from patients with mitochondrial diseases. The coexistence of their mitochondria within hybrids restored their normal morphology and respiratory enzyme activity by 10-14 days after fusion, indicating the presence of an extensive and continuous exchange of genetic contents between the mitochondria. This complementation between fused mitochondria may represent a defence of highly oxidative organelles against mitochondrial dysfunction caused by the accumulation of mtDNA lesions with age.

DNA, Mitochondrial↗

PubMed1999

Loss of the bcl-2 phosphorylation loop domain increases resistance of human leukemia cells (U937) to paclitaxel-mediated mitochondrial dysfunction and apoptosis.

The impact of ectopic expression of an N-terminal phosphorylation loop deletant Bcl-2 protein (Bcl-2Delta32-80) on the response of U937 monoblastic leukemia cells to paclitaxel was examined. In contrast to recent findings in HL-60 cells (Fang et al., Cancer Res. 58, 3202, 1998), U937 cells overexpressing Bcl-2Delta32-80 were significantly more resistant than those overexpressing full-length protein to caspase-3 and -9 activation, PARP degradation, and apoptosis induced by paclitaxel (500 nM; 18 h). Bcl-2Delta32-80 was also more effective than its full-length counterpart in opposing paclitaxel-mediated mitochondrial dysfunction, e.g., loss of mitochondrial membrane potential (Deltapsim) and cytochrome c release into the cytoplasm. Enhanced resistance of U937/Bcl-2Delta32-80 cells to paclitaxel was observed primarily in the G2M population. Together, these findings demonstrate that deletion of the Bcl-2 phosphorylation loop domain increases resistance of U937 leukemia cells to paclitaxel-mediated mitochondrial damage and apoptosis and suggest that factors other than, or in addition to, phosphorylation contribute to Bcl-2-related cytoprotectivity against paclitaxel in this model system.

Antineoplastic Agents, Phytogenic↗

PubMed2001

Endothelin-1 stimulates cardiomyocyte injury during mitochondrial dysfunction in culture.

To understand the pathophysiological role of endothelin-1 in the failing heart, we constructed a cellular mitochondrial impairment model and demonstrated the effect of endothelin-1. Primary cultured cardiomyocytes from neonatal rats were pretreated with rotenone, a mitochondrial complex I inhibitor, and the cytotoxic effect of endothelin-1 on the cardiomyocytes was demonstrated. Rotenone gradually decreased the pH of the culture medium with incubation time and caused slight cell injury. Endothelin-1 markedly enhanced the effect of rotenone that decreased the pH of the medium and enhanced cellular injury. The enhancement of the decrease in pH and cell injury induced by endothelin-1 was counteracted by the endothelin ET(A) receptor antagonist BQ123 or by maintaining the pH of the medium by the addition of 50 mM HEPES. Endothelin-1 markedly increased the uptake of 2-deoxyglucose and lactic acid production when the cardiomyocytes were pretreated with rotenone. These findings suggest that the stimulation of glucose uptake and anaerobic glycolysis followed by the increase in lactic acid accumulation in cardiomyocytes under the condition of mitochondrial impairment may be involved, at least in part, in the cellular injury by endothelin-1. Moreover, these findings suggest the possibility that the effect of endothelin-1 on myocardium is reversed by the condition of the mitochondria, and endogenous endothelin-1 may deteriorate cardiac failure with mitochondrial dysfunction. This may contribute to clarify the beneficial effect of endothelin receptor blockade in improving heart failures.

Animals↗

PubMed1994

Mitochondrial dysfunction in movement disorders.

A major theory regarding the mechanism of neuronal degeneration in several movement disorders is that mitochondrial defects may play a role. Biochemical studies in Parkinson's disease, Huntington's disease, multiple system atrophy, and idiopathic dystonia have shown defects in enzymes of oxidative phosphorylation in postmortem brain tissue, platelets, muscle, or lymphocytes. The basal ganglia and substantia nigra are also particularly susceptible to the accumulation of age-dependent mitochondrial DNA deletions, which may contribute to the delayed onset of movement disorders. The 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine model of Parkinson's disease involves conversion to 1-methyl-4-phenylpyridinium, which then inhibits complex I of the electron transport chain. Our studies show that the complex II inhibitor 3-nitropropionic acid can closely replicate the neurochemical, histologic, and clinical features of Huntington's disease. The mechanism of neuronal death in both these models may be slow excitotoxicity. Both direct biochemical studies and animal models of movement disorders therefore suggest that mitochondrial dysfunction may play a direct role in their pathogenesis.

Animals↗

PubMed2000

Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease.

A major risk factor for neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) is aging. Two processes that have been implicated in aging are free radical-induced oxidative damage and mitochondrial dysfunction. A progressive impairment of mitochondrial function and/or increased oxidative damage has been suggested to play critical roles in the pathogenesis of these neurodegenerative diseases. For example, decreased complex I activity, increased oxidative damage and altered activities of antioxidant defense enzymes have been demonstrated in PD. In AD, decrements in complex IV activity and increased oxidative damage have been reported. Reductions in complex II activity, increased cortical lactate levels and oxidative damage have been described in HD. Some familial ALS cases are associated with mutations in the gene for Cu,Zn superoxide dismutase (SOD1) while increased oxidative damage is observed in sporadic ALS. Studies in PSP have demonstrated regionally specific reductions in brain and muscle mitochondrial function, hypofrontality and increased oxidative damage. Altogether, the age-dependent onset and progressive course of these neurodegenerative diseases may ultimately highlight an association between aging, mitochondrial impairment and oxidative stress.

Aging↗

PubMed1996

Cocaine-induced mitochondrial dysfunction in primary cultures of rat cardiomyocytes.

Morphological alterations of cardiac mitochondria have been observed in rats chronically treated with cocaine. Whether cocaine directly causes heart mitochondrial dysfunction remains unclear. The present study was undertaken to investigate the effect of cocaine on mitochondrial function in cultured myocardial cells. Cells were incubated with cocaine (10(-5)-10(-3) M) for 3-72 h, using either a repeated or single exposure protocol. Cocaine (10(-3) M) produced severe cytotoxicity after repeated exposure (24-72 h), as elevated by leakage of lactate dehydrogenase. Treatment of the cultures with a single exposure protocol (10(-5)-10(-3) M for 24 h or less) produced a very modest cytotoxic effect, as shown by a small increase in LDH leakage. However, cellular ATP levels showed a time-dependent decline in cultures treated with the single exposure protocol. Experiments using a digitized fluorescence imaging system revealed that cocaine (single exposure protocol) caused a dose- and time-dependent decrease in mitochondrial membrane potential, and the decline in membrane potential occurred prior to manifestation of cytotoxicity shown with the repeated exposure protocol. Cytosolic and mitochondrial calcium levels, as determined by fura-2, were not affected during treatment with cocaine. Our results suggest that cocaine may compromise cardiac mitochondrial function and may lead to cardiotoxicity.

Adenosine Triphosphate↗

PubMed2002

Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.

A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded.

Adolescent↗

PubMed2001

Role of mitochondrial dysfunction in S-(1,2-dichlorovinyl)-l-cysteine-induced apoptosis.

The nephrotoxicity of trichloroethylene and dichloroacetylene has previously been linked to mitochondrial dysfunction induced by the metabolite S-(1,2-dichlorovinyl)-l-cysteine (DCVC). In this study, we examined whether key biochemical steps associated with mitochondria occur in DCVC-induced apoptosis in cultured porcine proximal tubular LLC-PK1 cells. DCVC caused a decrease in mitochondrial membrane potential (mt Delta Psi) beginning at 4 h and a release of cytochrome c into the cytoplasm at 6 h. Caspase-3-like activity was detected at 6 h and extensive DNA fragmentation was observed at 8 h. Decreases in cellular ATP were not evident until 8 h and later, even though electron microscopy showed that the mitochondria were extensively swollen. Aminooxyacetic acid (AOAA), an inhibitor of cysteine-conjugate beta-lyase, protected against mitochondrial changes and apoptosis. Overexpression of the antiapoptotic Bcl-2 protein desensitized LLC-PK1 cells to DCVC-induced apoptosis. These results support the interpretation that mitochondrial release of cyt c and cyt c-dependent activation of caspase-3 could have a central role in nephrotoxicity due to haloalkene-derived cysteine S-conjugates.

Aminooxyacetic Acid↗

PubMed1991

Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction.

Muscle biopsy specimens were obtained from 48 human immunodeficiency virus-infected patients suffering from various neuromuscular symptoms. Microscopic examination by conventional and electron microscopy revealed a characteristic structural myopathy associated with mitochondrial changes in 13 patients, all of whom had received long-term zidovudine therapy. The mean cumulative dose they had received (498 +/- 145 gm) was significantly higher than that of the other 14 zidovudine recipients of the study. They suffered from a progressive, usually painful, proximal myopathy with pronounced wasting, normal-to-moderately elevated creatine kinase levels, and a myopathic electromyographic pattern. The condition usually improved after withdrawal of the drug. Assay of mitochondrial enzymes, including succinate-cytochrome c reductase, cytochrome c oxidase, and citrate synthase, showed a decline in respiratory chain capacity. Southern blot analysis of mitochondrial DNA showed no abnormality. It is likely that mitochondrial dysfunction, probably resulting from drug-induced inhibition of the mitochondrial DNA polymerase, is implicated in the pathogenesis of this complication of zidovudine therapy.

Adult↗

PubMed2026

Beyond NAD Depletion: SARM1-Induced ATP Collapse Involves Direct ATP Degradation and Mitochondrial Dysfunction and Is Pharmacologically Reversible.

Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is an inducible NAD-consuming enzyme and execution factor in axon degeneration. Rapid ATP collapse after SARM1 activation, however, is not fully explained by NAD depletion alone. We used SARM1-overexpressing HEK293 cells and the cell-permeant activator CZ-48 to examine SARM1-induced non-apoptotic cell death, termed sarmoptosis. CZ-48 induced cell death that was suppressed by HSP90/70-annotated ATP-competitive compounds, especially geldanamycin and VER-155008 (VER), without reducing SARM1 abundance. VER preserved NAD and ATP during SARM1 activation but failed to rescue FK866-mediated NAD starvation, thereby distinguishing CZ-48/SARM1-driven cytotoxicity from generic NAD depletion. In cell-free assays, purified SARM1 reduced ATP levels; this effect was enhanced by SARM1's activator NMN and attenuated by its pharmacological inhibitors, although the in vitro activity was modest and the reaction products remain to be identified. ATPase-related perturbations, including thapsigargin and bafilomycin A1, also protected cells from CZ-48-induced death, further supporting a central role for ATP collapse in sarmoptosis. iTRAQ proteomics, MitoSOX Red staining, and DiOC6(3) staining revealed that CZ-48 treatment was associated with mitochondrial and metabolic remodeling, mitochondrial ROS accumulation, and mitochondrial depolarization, all of which were mitigated by VER. Collectively, these findings support a convergent ATP-collapse model in which SARM1 activation promotes NAD depletion, directly consumes ATP, and is associated with mitochondrial dysfunction that may amplify ATP-production failure.

ATP collapse↗

PubMed2026

A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization.

SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient's cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.

Humans↗

PubMed1998

Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction.

Oxidative stress is implicated in neuronal apoptosis that occurs in physiological settings and in neurodegenerative disorders. Superoxide anion radical, produced during mitochondrial respiration, is involved in the generation of several potentially damaging reactive oxygen species including peroxynitrite. To examine directly the role of superoxide and peroxynitrite in neuronal apoptosis, we generated neural cell lines and transgenic mice that overexpress human mitochondrial manganese superoxide dismutase (MnSOD). In cultured pheochromocytoma PC6 cells, overexpression of mitochondria-localized MnSOD prevented apoptosis induced by Fe2+, amyloid beta-peptide (Abeta), and nitric oxide-generating agents. Accumulations of peroxynitrite, nitrated proteins, and the membrane lipid peroxidation product 4-hydroxynonenal (HNE) after exposure to the apoptotic insults were markedly attenuated in cells expressing MnSOD. Glutathione peroxidase activity levels were increased in cells overexpressing MnSOD, suggesting a compensatory response to increased H2O2 levels. The peroxynitrite scavenger uric acid and the antioxidants propyl gallate and glutathione prevented apoptosis induced by each apoptotic insult, suggesting central roles for peroxynitrite and membrane lipid peroxidation in oxidative stress-induced apoptosis. Apoptotic insults decreased mitochondrial transmembrane potential and energy charge in control cells but not in cells overexpressing MnSOD, and cyclosporin A and caspase inhibitors protected cells against apoptosis, demonstrating roles for mitochondrial alterations and caspase activation in the apoptotic process. Membrane lipid peroxidation, protein nitration, and neuronal death after focal cerebral ischemia were significantly reduced in transgenic mice overexpressing human MnSOD. The data suggest that mitochondrial superoxide accumulation and consequent peroxynitrite production and mitochondrial dysfunction play pivotal roles in neuronal apoptosis induced by diverse insults in cell culture and in vivo.

Animals↗

PubMed2002

Role of ATP decrease in secretion induced by mitochondrial dysfunction in guinea-pig adrenal chromaffin cells.

The mechanism related to mitochondrial dysfunction-induced catecholamine (CA) secretion in dispersed guinea-pig adrenal chromaffin cells was investigated using amperometry and confocal laser microscopy. Application of CCCP, which does not stimulate generation of reactive oxygen species (ROS), reversibly induced CA secretion, whereas application of either cyanide or oligomycin (OL), a stimulator for ROS, enhanced CA secretion to a smaller extent. The CCCP-induced secretion was abolished by removal of external Ca2+ ions and was markedly diminished by D600. The mitochondrial membrane potential, measured using rhodamine 123, was rapidly lost in response to CCCP, but did not change noticeably during a 3 min exposure to OL. Prior exposure to OL markedly facilitated depolarization of the mitochondrial membrane potential in response to cyanide. The mitochondrial inhibitors rapidly produced an increase in Magnesium Green (MgG) fluorescence in the absence of external Ca2+ and Mg2+ ions, an increase that was larger in the cytoplasm than in the nucleus. The rank order of potency in increasing MgG fluorescence among the inhibitors was similar to that in increasing secretion. Thus, mitochondrial inhibition rapidly decreases [ATP] and the mitochondrial dysfunction-induced secretion is not due to ROS generation or to mitochondrial depolarization, but is possibly mediated by a decrease in ATP.

Adenosine Triphosphate↗

PubMed1994

Mitochondrial dysfunction during anoxia/reoxygenation injury of liver sinusoidal endothelial cells.

Sinusoidal endothelial cell injury plays a pivotal role in anoxia/reoxygenation liver damage. However, the mechanisms culminating in anoxia/reoxygenation endothelial cell injury remain unclear. Our aims were to determine whether anoxia/reoxygenation injury of sinusoidal endothelial cells causes mitochondrial dysfunction. In cultured rat liver sinusoidal endothelial cells, the mitochondrial membrane potential, cytosolic free calcium and cytosolic pH were quantitated by means of fluorescent probes and multiparameter digitized video microscopy. Cell viability was measured on the basis of lactate dehydrogenase release, and ATP was quantitated with a luciferin/luciferase assay. Mitochondrial membrane potential was stable during 90 min of aerobic perfusion. After 60 and 90 min of anoxia, mitochondrial membrane potential decreased gradually to 97% +/- 6% and 79% +/- 7% of the basal value, respectively. However, mitochondrial membrane potential decreased abruptly with reoxygenation after 60 min of anoxia to 45% +/- 12% of the basal value and did not recover over 30 min of aerobic perifusion. Loss of mitochondrial membrane potential could not be attributed to changes of cytosolic free calcium, cytosolic pH, nitric oxide generation or activity of poly(ADP-ribose) polymerase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1991

Mitochondrial dysfunction in multiple symmetrical lipomatosis.

Multiple symmetrical lipomatosis is a striking clinical finding associated with a variety of peripheral and central nervous system abnormalities. We describe 4 unrelated patients with evidence of mitochondrial dysfunction in skeletal muscle. Multiple symmetrical lipomatosis is an additional, albeit unusual, manifestation of the expanding clinical spectrum of mitochondrial diseases.

Adult↗