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PubMed2005

No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA.

Accumulation of high levels of mutagenic oxidative mitochondrial DNA (mtDNA) lesions like 8-oxodeoxyguanine (8-oxodG) is thought to be involved in the development of mitochondrial dysfunction in aging and in disorders associated with aging. Mice null for oxoguanine DNA glycosylase (OGG1) are deficient in 8-oxodG removal and accumulate 8-oxodG in mtDNA to levels 20-fold higher than in wild-type mice (N.C. Souza-Pinto et al., 2001, Cancer Res. 61, 5378-5381). We have used these animals to investigate the effects on mitochondrial function of accumulating this particular oxidative base modification. Despite the presence of high levels of 8-oxodG, mitochondria isolated from livers and hearts of Ogg1-/- mice were functionally normal. No differences were detected in maximal (chemically uncoupled) respiration rates, ADP phosphorylating respiration rates, or nonphosphorylating rates with glutamate/malate or with succinate/rotenone. Similarly, maximal activities of respiratory complexes I and IV from liver and heart were not different between wild-type and Ogg1-/- mice. In addition, there was no indication of increased oxidative stress in mitochondria from Ogg1-/- mice, as measured by mitochondrial protein carbonyl content. We conclude, therefore, that highly elevated levels of 8-oxodG in mtDNA do not cause mitochondrial respiratory dysfunction in mice.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1991

The cardioprotective effect of gamma-glutamylcysteine ethyl ester during coronary reperfusion in canine hearts.

1. The cardioprotective effect of gamma-glutamylcysteine ethyl ester was investigated on ischaemia-reperfusion-induced myocardial damage in anaesthetized dogs. 2. Open chest anaesthetized dogs were divided into four groups: 2 h occlusion of the left anterior descending coronary artery (LAD); 2 h LAD occlusion followed by 1 h reperfusion; 2 h LAD occlusion followed by 1 h reperfusion with administration of gamma-glutamylcysteine ethyl ester (10 mg kg-1 just before reperfusion); 2 h LAD occlusion followed by 1 h reperfusion with administration of GSH (the reduced form of glutathione, 10 mg kg-1 just before reperfusion). 3. After occlusion or reperfusion, heart mitochondria were prepared from the normal area and the occluded or the reperfused area, and mitochondrial function (rate of oxygen consumption in State III, and respiratory control index) was measured polarographically. 4. Mitochondrial GSH and GSSG (the oxidized form of glutathione) concentrations, and activities of glutathione peroxidase and glutathione reductase were measured. 5. Two h of LAD occlusion induced mitochondrial dysfunction with depletion of mitochondrial GSH concentration. One h of reperfusion after 2 h LAD occlusion induced significant mitochondrial dysfunction associated with a marked depletion of mitochondrial GSH concentration. 6. gamma-Glutamylcysteine ethyl ester reduced mitochondrial dysfunction and depletion of mitochondrial GSH concentration after 2 h LAD occlusion and 1 h reperfusion. In contrast, GSH did not prevent depletion of mitochondrial GSH concentration and mitochondrial dysfunction after 2 h LAD occlusion followed by 1 h reperfusion. 7. The activities of glutathione peroxidase and glutathione reductase did not change significantly in each group. 8. One h of reperfusion after 2 h occlusion of LAD induced ventricular arrhythmias. gamma-Glutamylcysteine ethyl ester markedly reduced the development of reperfusion arrhythmias, whilst GSH showed no protective effect.9. Gamma-Glutamylcysteine ethyl ester maintained mitochondrial GSH concentration, prevented reperfusion myocardial damage, and reduced reperfusion arrhythmias.

Animals↗
PubMed2006

[Influence of diabetes mellitus on cerebral ischemia and reperfusion injury].

Cerebral ischemia, caused by disturbance of the blood supply to the brain, is a major cause of death in our days. Diabetes mellitus exacerbates neuronal death induced by an ischemic insult. It is important to characterize the underlying mechanism of the cell damage in order to design therapeutic agents. The purpose of this study is to summarize some of the intracellular events leading to aggravated cell injury after diabetic ischemia including mitochondrial dysfunction. Release of mitochondrial cytochrome c activates the cell death executioner caspase-3 protease resulting in the cleavage of poly-ADP ribose polymerase (PARP) involved in DNA repair. Mitochondrial dysfunction is associated with enhanced production of free radicals such as superoxide anion, nitric oxide and peroxynitrite after diabetic ischemic injury. Mitochondrial dysfunction affects not only neurons but also astrocytes, which play an important role in neuronal functions. Damage of these cells participates in the exaggerated brain damage after cerebral ischemia. In summary, diabetes mellitus enhances intracellular pathways activated by cerebral ischemia and leads to exaggerated brain damage in diabetic subjects.

Astrocytes↗
PubMed2003

Investigation of mitochondrial function in hereditary spastic paraparesis.

Following the association of hereditary spastic paraparesis (HSP) with mutation in the paraplegin gene (SPG7) and mitochondrial dysfunction, we wished to investigate whether mitochondrial dysfunction might be associated with other forms of HSP. Five cases of HSP caused by mutation in the spastin gene (SPG4) and nine cases with HSP with mutation in the spastin and paraplegin genes excluded (non-SPG4/SPG7), were investigated for mitochondrial dysfunction. Muscle tissue from the HSP groups and a control group was analysed histochemically and spectrophotometrically for mitochondrial dysfunction. A significant decrease in mitochondrial respiratory chain complexes I and IV was demonstrated in the non-SPG4/SPG7 group. No abnormality was detected in the SPG4 group. We therefore conclude that there is evidence for mitochondrial dysfunction in non-SPG4/SPG7 HSP. There is no evidence for mitochondrial dysfunction in the pathogenesis of spastin-related HSP.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2005

Lactate stress testing in sporadic amyotrophic lateral sclerosis.

Mitochondrial dysfunction is frequently observed in ALS. Mitochondrial dysfunction may result in increased serum lactate at rest or low levels of exercise, being used for diagnostic purposes. The study investigated if resting-lactate-determination is superior to lactate-stress-testing (LST) in demonstrating mitochondrial dysfunction in ALS. Included were 15 ALS patients, 4 women, 11 men, aged 37-72. Severity of the disease was assessed by the Norris-score. The control group comprised 66 healthy subjects, 40 women, 26 men, aged 36-76. Serum lactate was determined before, three times during, and once after a constant workload with 30 W on a bicycle ergometer. According to the EIEscorial criteria 8 patients had definite, 4 probable, 3 possible ALS. Resting lactate was increased in 2 patients, 1 with definite and 1 with possible ALS. The LST was abnormal in 5 patients with definite, 1 with probable and 1 with possible ALS. The mean Norris-score was 67.8 in patients with abnormal LST and 74.6 in patients with normal LST. In conclusion, the LST is more suitable than resting-lactate-determination in demonstrating mitochondrial dysfunction in ALS. The LST suggests mitochondrial dysfunction in half of the ALS patients. Mitochondrial dysfunction in ALS is related to the clinical severity of the disease.

Acidosis, Lactic↗
PubMed1999

Role and mechanisms of secondary mitochondrial failure.

Ischemia is accompanied by mitochondrial dysfunction, as assessed by measurements of mitochondrial respiratory activities in vitro. Following brief periods of ischemia, mitochondrial function is usually normalized during reperfusion. However, particularly after ischemia of longer duration, reperfusion may be accompanied by secondary mitochondrial failure. After short periods of ischemia this is observed in selectively vulnerable areas and, after intermediate to long periods of ischemia, in other areas as well. However, it has remained unsettled if the mitochondrial dysfunction is the result or the cause of cell death. Although it has been commonly assumed that such failure is secondary to cell injury by other mechanisms, recent results suggest that mitochondrial dysfunction may be the cause of cell death. Indirect evidence for this postulate is provided by experiments showing that cyclosporin A (CsA), when allowed to cross the blood-brain barrier, is a potent neuroprotectant. CsA is a virtually specific blocker of the mitochondrial permeability transition (MPT) pore, a voltage-gated channel allowing molecules and ions with a mass < 1500 Daltons to pass the inner mitochondrial membrane. Experiments on isolated cells in vitro demonstrate that cell calcium accumulation or oxidative stress triggers the assembly of an MPT pore, which leads to collapse of the mitochondrial membrane potential, to ATP hydrolysis, to enhanced production of reactive oxygen species (ROS), and to cell death. The beneficial effect of CsA could thus be related to its ability to block the MPT pore. Longer periods of ischemia, such as occurs after transient middle cerebral artery (MCA) occlusion, lead to pan-necrotic lesions (infarction). In the rat, recirculation following 2 h of MCA occlusion leads to partial normalization of the bioenergetic state but this is followed within 4-6 h by secondary bioenergetic failure. The latter seems unrelated to blockade of the microcirculation, but correlates to secondary mitochondrial failure. The brain damage incurred is ameliorated by the spin trap alpha-phenyl-N-butyl nitrone (PBN) and by the immunosuppressant FK506 even when given 1-3 h after the start of recirculation. The two drugs also prevent the secondary mitochondrial failure during early recirculation, suggesting that such failure is pathogenetically important. Probably, though, the mitochondrial dysfunction involves not only the assembly of an MPT pore but also other mechanisms. Since recirculation is associated with release of mitochondrial proteins it is not unlikely that such proteins, e.g. cytochrome c, trigger cascades of events leading to cell death.6.

Animals↗
PubMed2005

Bid is upstream of lysosome-mediated caspase 2 activation in tumor necrosis factor alpha-induced hepatocyte apoptosis.

BACKGROUND & AIMS: During tumor necrosis factor alpha-mediated hepatocyte cytotoxicity, cathepsin B is released from lysosomes and contributes to apoptosis by indirectly promoting mitochondrial dysfunction. How this lysosomal pathway mediates mitochondrial dysfunction is unclear. Because Bcl-2 family proteins and caspase 2 have been implicated in proximal apoptosis-signaling pathways, we examined the role of these proteins in tumor necrosis factor alpha-induced lysosomal permeabilization and cathepsin B-mediated mitochondrial dysfunction. METHODS: Studies were performed in primary hepatocytes from wild-type cathepsin B knockout, Bid knockout, and caspase 2 knockout mice and in the rat hepatoma cell line McArdle7777 by using tumor necrosis factor alpha/actinomycin D. RESULTS: Studies in wild-type and Bid knockout hepatocytes showed that tumor necrosis factor alpha-mediated lysosomal permeabilization is Bid dependent. After tumor necrosis factor alpha/actinomycin D treatment, caspase 2 activity increased severalfold in wild-type hepatocytes, whereas minimal activity was observed in hepatocytes from cathepsin B knockout mice or in hepatoma cells treated with a cathepsin B inhibitor. In contrast, Bax was activated independently of cathepsin B. Pharmacological, genetic, or small interfering RNA-mediated inhibition of caspase 2 attenuated tumor necrosis factor alpha-mediated mitochondrial dysfunction, downstream caspase activation, and hepatocyte apoptosis. CONCLUSIONS: These data suggest that tumor necrosis factor alpha triggers Bid-dependent lysosomal permeabilization, followed by release of cathepsin B into the cytosol and activation of caspase 2. Caspase 2 then facilitates efficient mitochondrial cytochrome c release and apoptosis.

Animals↗
PubMedDate not supplied

The contribution of mitochondria to common disorders.

Mitochondrial dysfunction secondary to mitochondrial and nuclear DNA mutations has been associated with energy deficiency in multiple organ systems and a variety of severe, often fatal, clinical syndromes. Although the production of energy is indeed the primary function of mitochondria, attention has also been directed toward their role producing reactive oxygen and nitrogen species and the subsequent widespread deleterious effects of these intermediates. The generation of toxic reactive intermediates has been implicated in a number of relatively common disorders, including neurodegenerative diseases, diabetes, and cancer. Understanding the role mitochondrial dysfunction plays in the pathogenesis of common disorders has provided unique insights into a number of diseases and offers hope for potential new therapies.

DNA, Mitochondrial↗
PubMed2006

Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes.

OBJECTIVE: To compare the electrophysiological and histopathological features of immunological myasthenia gravis (MG) subtypes. METHODS: Fifty MG patients underwent clinical examination, MuSK-Ab and AChR-Ab analysis. The majority underwent quantitative and single-fiber electromyography (QEMG, SFEMG), repetitive nerve stimulation and deltoid muscle biopsy. From muscle specimens with histological mitochondrial dysfunction, we amplified mitochondrial DNA (mtDNA). In specimens with mtDNA deletions, the nuclear gene POLG1 was sequenced. RESULTS: Five AChR-Ab seropositive [AChR(+)] and 5 seronegative [AChR(-)] patients were MuSK-Ab seropositive [MuSK(+)]. Five of 7 neurophysiologically examined MuSK(+) patients (71%) had proximal myopathic pattern, compared to 7 of 31 MuSK(-)/AChR(+) patients (23%) (P=0.012). SFEMG was abnormal in all examined MuSK(+) patients. All 7 biopsied MuSK(+) and 32 MuSK(-) patients (89%) had cytochrome c oxidase (COX) negative fibers. Three of five MuSK(+) and 13 of 20 MuSK(-) patients analyzed had multiple mtDNA deletions but no POLG1 mutations. CONCLUSIONS: Similar degree of SFEMG abnormalities was present in proximal muscles among MuSK(+) and AChR(+) patients. Proximal myopathy was over-represented in MuSK(+) patients; however, both MuSK(+) and MuSK(-) patients had mild myopathy with frequent mitochondrial abnormalities. SIGNIFICANCE: The weakness in MuSK(+) patients is most likely due to disturbed neuromuscular transmission. The frequently encountered mitochondrial dysfunction in MG warrants further study.

Action Potentials↗
PubMed2006

Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats.

Increased oxidative/nitrosative stress is a major contributing factor to alcohol-mediated mitochondrial dysfunction. However, which mitochondrial proteins are oxidatively modified under alcohol-induced oxidative/nitrosative stress is poorly understood. The aim of this study was to systematically investigate oxidized and/or S-nitrosylated mitochondrial proteins and to use a biotin-N-maleimide probe to evaluate their inactivation in alcoholic fatty livers of rats. Binge or chronic alcohol exposure significantly elevated nitric oxide, inducible nitric oxide synthase, and ethanol-inducible CYP2E1. The biotin-N-maleimide-labeled oxidized and/or S-nitrosylated mitochondrial proteins from pair-fed controls or alcohol-fed rat livers were subsequently purified with streptavidin-agarose. The overall patterns of oxidized and/or S-nitrosylated proteins resolved by 2-dimensional polyacrylamide gel electrophoresis were very similar in the chronic and binge alcohol treatment groups. Seventy-nine proteins that displayed differential spot intensities from those of control rats were identified by mass spectrometry. These include mitochondrial aldehyde dehydrogenase 2 (ALDH2), ATP synthase, acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase, and many proteins involved in chaperone activity, mitochondrial electron transfer, and ion transport. The activity of 3-ketoacyl-CoA thiolase involved in mitochondrial beta-oxidation of fatty acids was significantly inhibited in alcohol-exposed rat livers, consistent with hepatic fat accumulation, as determined by biochemical and histological analyses. Measurement of activity and immunoblot results showed that ALDH2 and ATP synthase were also inhibited through oxidative modification of their cysteine or tyrosine residues in alcoholic fatty livers of rats. In conclusion, our results help to explain the underlying mechanism for mitochondrial dysfunction and increased susceptibility to alcohol-mediated liver damage.

Animals↗
PubMed2006

Proteomic analysis of cellular change involved in mitochondria-to-nucleus communication in L6 GLUT4myc myocytes.

Genetic or biochemical abnormalities in mitochondria are closely associated with apoptosis, aging, cancer, and other chronic degenerative diseases. Mitochondrial dysfunction resulting from mitochondrial DNA (mtDNA) depletion dispatches retrograde signals to the nucleus to compensate by altering the expression of various genes. In this study, a proteomic approach was used to gain insight into the nuclear gene targets of mitochondrial stress signaling and the pathophysiological mechanisms associated with mitochondrial dysfunction. We have used 2-DE to characterize the nuclear gene responses resulting from mtDNA depletion in L6 GLUT4myc myocytes. Our results showed that 77 polypeptides were differentially expressed in mtDNA-depleted cells; 33 polypeptides were down-regulated and 44 polypeptides were up-regulated. Of these differentially expressed polypeptides, 40 were identified as 36 different proteins by MALDI-TOF MS. These proteins are related to various cellular responses, such as apoptosis, cellular metabolism, signaling and cytoskeleton functions. It is suggested that the insulin resistance developed in mtDNA-depleted myocytes may be associated with disorganization of cytoskeleton assembly, and that cellular mtDNA depletion might promote the ability to evade apoptosis or other death effectors.

Animals↗
PubMed2005

In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA.

BACKGROUND: Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described. METHODS: We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks. RESULTS: We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues. CONCLUSIONS: Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.

Adipose Tissue↗
PubMed2006

Malonaldehyde acts as a mitochondrial toxin: Inhibitory effects on respiratory function and enzyme activities in isolated rat liver mitochondria.

Malonaldehyde (MDA) is a product of oxidative damage to lipids, amino acids and DNA, and accumulates with aging and diseases. MDA can possibly react with amines to modify proteins to inactivity enzymes and also modify nucleosides to cause mutagenicity. Mitochondrial dysfunction is a major contributor to aging and age-associated diseases. We hypothesize that accumulated MDA due to mitochondrial dysfunction during aging targets mitochondrial enzymes to cause further mitochondrial dysfunction and contribute to aging and age-associated diseases. We investigated the effects of MDA on mitochondrial respiration and enzymes (membrane complexes I, II, III and IV, and dehydrogenases, including alpha-ketoglutaric dehydrogenase (KGDH), pyruvate dehydrogenase (PDH), malate dehydrogenase (MDH)) in isolated rat liver mitochondria. MDA showed a dose-dependent inhibition on mitochondrial NADH-linked respiratory control ratio (RCR) and ADP/O ratio declined from the concentrations of 0.2 and 0.8 micromol/mg protein, respectively, and succinate-linked mitochondrial RCR and ADP/O ratio declined from 1.6 and 0.8 micromol/mg protein. MDA also showed dose-dependent inhibition on the activity of PDH, KGDH and MDH significantly from 0.1, 0.2 and 2 micromol/mg protein, respectively. Activity of the complexes I and II was depressed by MDA at 0.8 and 1.6 micromol/mg protein. However, MDA did not affect activity of complexes III and IV in the concentration range studied (0-6.4 micromol/mg protein). These results suggest that MDA can cause mitochondrial dysfunction by inhibiting mitochondrial respiration and enzyme activity, and the sensitivity of the enzymes examined to MDA is in the order of PDH>KGDH>complexes I and II>MDH>complexes III and IV.

Aging↗
PubMed1999

Mitochondria, NO and neurodegeneration.

A role for mitochondrial dysfunction in neurodegenerative disease is gaining increasing support. Mitochondrial dysfunction may be linked to neurodegenerative diseases through a variety of different pathways, including free-radical generation, impaired calcium buffering and the mitochondrial permeability transition. This can lead to both apoptotic and necrotic cell death. Recent evidence has shown that there is a mitochondrial defect in Friedreich's ataxia, which leads to increased mitochondrial iron content, that appears to be linked to increased free-radical generation. There is evidence that the point mutations in superoxide dismutase which are associated with amyotrophic lateral sclerosis may contribute to mitochondrial dysfunction. There is also evidence for bioenergetic defects in Huntington's disease. Studies of cybrid cell lines have implicated mitochondrial defects in both Parkinson's disease and Alzheimer's disease. If mitochondrial dysfunction plays a role in neurodegenerative diseases then therapeutic strategies such as coenzyme Q10 and creatine may be useful in attempting to slow the disease process.

Humans↗
PubMed2005

Cerebral MR imaging in uninfected children born to HIV-seropositive mothers and perinatally exposed to zidovudine.

BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been reported in HIV-negative children perinatally exposed to zidovudine, a drug often used in HIV-seropositive mothers during pregnancy. The purpose of this study was to determine the incidence of cerebral MR imaging findings in HIV-uninfected children exposed to zidovudine who present with unexplained neurologic symptoms. METHODS: Two expert groups conducted a systematic, retrospective review of all cerebral MR images available in a multicentric, nationwide French prospective cohort of children born to HIV-seropositive mothers to identify imaging abnormalities. Experts were blinded to each others' interpretations, to the children's neurologic symptoms, and to laboratory evidence of mitochondrial dysfunction. The incidence of abnormalities was determined and compared with the neurologic presentation and laboratory evidence of mitochondrial dysfunction. RESULTS: MR images from 49 HIV-uninfected children (mean age, 26 months) were available for study. All children were perinatally exposed to zidovudine. Twenty-two had probable or established mitochondrial dysfunction according to their symptoms and laboratory data. Twenty-seven children without mitochondrial dysfunction presented with unexplained neurologic symptoms (n = 14) or nonneurologic symptoms (n = 7), and six were asymptomatic. Sixteen of 22 MR images in children with mitochondriopathy were considered abnormal in both independent analyses. Diffuse hyperintensity in the supratentorial white matter (n = 9) and in the tegmentum pons (n = 9) were the most frequent anomalies. Imaging abnormalities were often multifocal (n = 10) and sometimes associated with necrotic areas (n = 3) and volume loss (n = 8). Although 19 of 27 MR images of children without mitochondrial dysfunction were mainly normal, abnormal images were observed in five of 14 children with unexplained neurologic symptoms and in three of six asymptomatic children. CONCLUSION: Images observed in children with antiretroviral-induced mitochondrial dysfunction are similar to those observed in congenital mitochondrial diseases. These images were also observed in symptomatic or asymptomatic children without evidence of systemic mitochondrial dysfunction.

Anti-HIV Agents↗
PubMed2002

A colony color method identifies the vulnerability of mitochondria to oxidative damage.

Mitochondrial dysfunction is a profound feature of cancer cells and is also known to cause several mitochondrial diseases. Mutations in mitochondrial DNA (mtDNA) have been reported frequently in these diseases. Although many environmental agents are known to cause damage to mitochondria, rapid methods need to be developed for testing agents that cause mitochondrial dysfunction and are involved in the development of mitochondrial and other diseases. Using Saccharomyces cerevisiae, we describe the development of a colorimetric method that identifies both physical and chemical agents that cause mitochondrial dysfunction and mutation of the mitochondrial genome. This method utilizes the previously reported ade2 mutant of S.cerevisiae that produces red colonies. However, when they lose mitochondrial function the colonies turn white. This colorimetric method has helped quantify the vulnerability of mtDNA to oxidative agents. Our study reveals that the oxidative agent adriamycin causes both mutation and extensive damage to mtDNA, which leads to loss of mtDNA. Our study also reveals that the lost mtDNA fragments migrate to the nucleus and integrate into the nuclear genome. Furthermore, our analysis reveals that loss of mtDNA leads to resistance to oxidative agents. The method described in this paper should aid in the rapid identification of environmental and other agents that cause mitochondrial dysfunction and mutagenesis, agents that may be involved in the development of mitochondrial and other diseases.

Adenine↗
PubMed2001

Endothelin-1 production is enhanced by rotenone, a mitochondrial complex I inhibitor, in cultured rat cardiomyocytes.

In chronic heart failure and acute myocardial infarction, the tissue level of endothelin (ET)-1 in the heart, as well as its plasma level, has been reported to increase markedly. There is, however, little information about what in these pathologic conditions leads to increased production of ET-1, and which type of cell in the heart produces ET-1. We examined the mRNA and peptide expression of ET-1 using cultured rat neonatal cardiomyocytes, in which mitochondrial dysfunction was induced by rotenone, a mitochondrial respiratory chain complex I inhibitor, because one of the common features in failing or ischemic hearts is an alteration in energy metabolism due to mitochondrial dysfunction. Rotenone increased glucose use by the culture cells within 12 h of addition without affecting cell viability, and depressed the mitochondrial membrane potential after 72 h, indicating the induction of mitochondrial dysfunction in cardiomyocytes. Rotenone induced significant increase in the expression level of mRNA for ET-1 within 1 h of addition. In accordance with this finding, immunoreactive ET-1 in culture medium increased 3 times after 24 h of incubation, suggesting active secretion of ET-1 from cultured cells treated with rotenone. Immunocytochemical analysis verified significant increase of ET-1 peptide in cardiomyocytes, confirming the production of ET-1 by cardiomyocytes. These results suggest that derangement of mitochondrial function in cardiomyocytes itself could lead to the increased production of ET-1 in cardiomyocytes, and that this mechanism may contribute to the increased production of ET-1 in failing and ischemic hearts.

Animals↗
PubMed2004

S-Adenosylmethionine protects against acetaminophen-induced hepatotoxicity in mice.

An overdose of acetaminophen (APAP) is the most frequent cause of fulminant liver failure in the United States. Increasing evidence demonstrates that oxidative stress plays an important etiologic role in APAP-induced liver injury. S-Adenosylmethionine (SAMe) is a key intermediate in the hepatic trans-sulfuration pathway and serves as a precursor for glutathione (GSH) as well as the methyl donor in most transmethylation reactions. In the present study, we investigated effects of SAMe on liver injury induced by APAP administration in male C57BL/6 mice. Two related studies were performed. In the first experiment, SAMe (1g/kg BW) was injected intraperitoneally 4 h before APAP (600 mg/kg BW) administration. In the second experiment, SAMe was injected intraperitoneally 1 h after APAP administration. Our results showed that APAP administration induced changes typical of confluent centrilobular necrosis by histological examination and a marked elevation in serum alanine aminotransferase (ALT) activity. APAP administration induced significant decreases in both hepatic and blood SAMe concentrations. In addition, APAP decreased intracellular (both cytosolic and mitochondrial) GSH concentrations along with increased lipid peroxidation in conjunction with mitochondrial dysfunction as documented by Ca2+-induced mitochondrial permeability transition. SAMe treatment (both before and after APAP) significantly attenuated the liver injury. Exogenous SAMe prevented the decrease in liver and blood SAMe concentrations. Moreover, SAMe treatment attenuated both cytosolic and mitochondrial GSH depletion as well as mitochondrial dysfunction. We conclude that SAMe at least in part protects the liver from APAP-induced injury by preventing intracellular GSH depletion and mitochondrial dysfunction.

Acetaminophen↗