SEARCH · PubMed Health

Results for “Mitochondria dysfunction”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 1,153 records · Page 64Linked to original sources

PubMed2006

Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy.

BACKGROUND: Tenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddl), their concurrent use was also investigated. DESIGN: Relative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+ individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+ individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV-,n=22). Twelve of the HIV+/TDF+ individuals received concurrent ddl, 10 of those once at unadjusted ddl dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests. RESULTS: Kidney mtDNA levels were different among the three groups (P=0.046). mtDNA ratios were lower in HIV+/TDF+ subjects (7.5 [2.0-12.1]) than in HIV- ones (14.3 [6.0-16.5], P=0.014), but not lower than HIV+/TDF- controls (6.4 [2.8-11.9], P=0.82). Among HIV+ subjects, there was a difference between TDF-, TDF+/ddl- and TDF+/ddl+ (P=0.005), with concurrent TDF/ddl use associated with lower mtDNA (2.1 [1.9-5.5], n=12) than TDF+/ddl- (13.8 [7.5-16.4], n=9, P=0.003). No TDF-/ddl+ biopsies were available. In regression analyses, only HIV infection (P=0.03), and TDF/ddl use (P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+ biopsies than HIV+/TDF- and HIV- ones together (P<0.001) but not more so in TDF+/ddl+ biopsies than TDF+/ddl- ones (P=0.67). CONCLUSIONS: Renal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddl therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddl may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddl when used in conjunction with TDF.

Adenine↗

PubMed2002

Mitochondrial oxidative metabolism in motor neuron degeneration (mnd) mouse central nervous system.

The mnd mouse spontaneously develops slowly evolving motoneuron pathology leading to progressive motor impairment. There is strong evidence that a complex interplay between oxidative stress, mitochondria abnormalities and alteration of glutamate neurotransmission plays an important role in the pathogenesis of motor neuron diseases. Therefore, we investigated the presence of mitochondrial dysfunction in frontal, central (comprising the motor area) and occipital regions of the cerebral cortex and in the spinal cord of 35-week-old mnd mice. Lipid peroxide derivatives reacting with thiobarbituric acid (TBARS) were measured in the cervical, thoracic and lumbar spinal cord. In addition biochemical and behavioural analyses were carried out in mnd mice chronically treated with l-carnitine from the 11th to the 34th week of life (mndT mice). Slight but significant alterations of mitochondrial enzyme activities were seen in the mnd cortical regions. The central area was the most affected and both complex I, IV and citrate synthase were decreased with respect to controls. The rate of oxygen consumption (QO2) was markedly decreased in both the upper (cervical + upper portion of the thoracic region) and lower (lumbar + lower portion of the thoracic region) mnd spinal cord. The level of TBARS showed a rostro-caudal trend to increase, being 30% higher in the lumbar tract of mnd mice in comparison with controls. L-carnitine treatment increased the mitochondrial enzyme activities in cortical regions towards control value and was effective in enhancing QO2 and decreasing TBARS levels in the spinal cord of mndT. Behavioural testing showed that L-carnitine significantly delayed the onset of motor behaviour impairment. This beneficial effect was declining at 35 week of age, when the biochemical measurements were performed.

Age Factors↗

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↗

PubMed2003

Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction.

Manganese ethylene-bis-dithiocarbamate (Mn-EBDC) is the major active element of maneb, a pesticide linked to parkinsonism in certain individuals upon chronic exposure. Additionally, it has been shown to produce dopaminergic neurodegeneration in mice systemically coexposed to another pesticide, 1,1'-dimethyl-4,4'-bipyridinium (paraquat). Here, we described a rat model in which selective dopaminergic neurodegeneration was produced by delivering Mn-EBDC directly to the lateral ventricles. After establishing this model, we tested whether Mn-EBDC provoked dopamine efflux in the striatum, a well-known phenomenon produced by the mitochondrial inhibitor 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that causes parkinsonism in humans, as well as in some animals. Finally, we investigated whether Mn-EBDC directly inhibited mitochondrial function in vitro using isolated brain mitochondria. Our data demonstrated that Mn-EBDC induced extensive striatal dopamine efflux that was comparable with that induced by MPP+, and that Mn-EBDC preferentially inhibited mitochondrial complex III. As mitochondrial dysfunction is pivotal in the pathogenesis of Parkinson's disease (PD), our results support the proposal that exposure to pesticides such as maneb, or other naturally occurring compounds that inhibit mitochondrial function, may contribute to PD development.

Animals↗

PubMed2004

Oxidation of vitamin E and vitamin C and inhibition of brain mitochondrial oxidative phosphorylation by peroxynitrite.

The effects of peroxynitrite (PN; product of the reaction between nitric oxide and superoxide) on mitochondrial respiration as well as oxidation of alpha-tocopherol and ascorbic acid were studied. Mitochondria were isolated from brain hemispheres of 4-month-old male Fisher rats by standard centrifugation procedures utilizing Ficoll gradients. Treatment of brain mitochondria with PN caused a concentration-dependent impairment of oxidative phosphorylation and depletion of the endogenous antioxidants alpha-tocopherol and ascorbic acid. PN-induced mitochondrial dysfunction was characterized by 1) decreases in state 3 respiration and oxidative phosphorylation, 2) loss of respiratory control [ratio of ADP-stimulated (state 3) to basal (state 4) respiration], and 3) uncoupling of oxidative phosphorylation. PN did not function as a pure uncoupler, insofar as the increase in state 4 respiration was accompanied by a larger decrease in state 3 respiration. This contrasts with the uncoupling action of the protonophore carbonyl cyanide m-chlorophenylhydrozone, which increases both state 3 and state 4 respiration. PN-induced reduction in respiratory control and oxidative phosphorylation closely paralleled the oxidation of membrane tocopherol and were preceded by loss of ascorbate. alpha-Tocopherol (the most potent biological lipid antioxidant) may have a unique role in protecting mitochondrial membranes from oxidative stress. The two antioxidant nutrients alpha-tocopherol and ascorbate (which interact with each other and glutathione) may be intimately involved in protecting mitochondria in situations in which excessive release of superoxide and nitric oxide occurs under normal and/or pathological conditions.

Animals↗

PubMed2004

Impairment of mitochondrial oxidative phosphorylation in rat fatty liver exposed to preservation-reperfusion injury.

BACKGROUND/AIMS: As the impairment of the cellular energy metabolism contributes to the failure of fatty liver grafts after transplantation, we aimed to determine whether steatosis affects the oxidative phosphorylation activity during preservation. METHODS: Rat normal and fatty livers were preserved for 18 h and then reperfused with warm oxygenated solution. The oxidative phosphorylation, the F(0)F(1)-ATPase and the Complex I activities were assessed in isolated mitochondria before and after preservation, and during reperfusion. The ALT release and portal pressure were monitored during reperfusion. RESULTS: The baseline phosphorylation activity was similar in normal and steatotic mitochondria. After cold preservation, the respiratory control index and state 3 respiration decreased significantly only in steatotic livers. Reperfusion induced a further deterioration in either group. Contrary to normal liver, uncoupling of fatty liver mitochondria allowed the recovery of the maximal respiration rate only using succinate (Complex II-dependent substrate), but not glutamate-malate (Complex I-dependent). Complex I dysfunction was confirmed spectrophotometrically. The ATPase activity was also significantly lower in fatty livers. Finally, ALT release and portal pressure were greater in steatotic livers. CONCLUSIONS: The alteration of the oxidative phosphorylation activity during preservation is greatly exacerbated by fatty infiltration likely resulting from damage of the respiratory chain Complex I and of the F(0)F(1)-ATP synthase.

Adenosine Triphosphate↗

PubMed2003

Mitochondria-targeting therapeutic strategies for overcoming chemoresistance and progression of cancer.

The cytotoxic effects of many anticancer drugs are mediated via the apoptotic pathways. Chemoresistant tumor cells have acquired the ability to evade the action of multiple classes of anti-cancer drugs. One mechanism by which tumor cells survive in the presence of chemotherapy is by increasing anti-apoptotic activities. Since mitochondria are critical 'gatekeepers' to the apoptosis process, development of cytotoxic drugs that target mitochondria may provide a new strategy to induce apoptosis in tumor cells. Mitochondrial permeability transition pore complex (PTPC) controls mitochondrial membrane permeabilization, which is a critical event in the process leading to chemotherapy-induced apoptosis. Therefore, targeting of PTPC components may overcome chemoresistance in tumor cells. Moreover, alterations in mitochondrial DNA such as mutation and the subsequent dysfunction of mitochondrial respiratory enzyme have been reported in various types of cancer, and their functional consequences are associated cancer development, chemoresistance, and therapeutic implications. In this mini-review, we aim to provide a brief review on several mitochondria-targeting strategies to overcome chemoresistance in cancer.

Animals↗

PubMedDate not supplied

Mitochondrial inhibition and oxidative stress: reciprocating players in neurodegeneration.

Although the etiology for many neurodegenerative diseases is unknown, the common findings of mitochondrial defects and oxidative damage posit these events as contributing factors. The temporal conundrum of whether mitochondrial defects lead to enhanced reactive oxygen species generation, or conversely, if oxidative stress is the underlying cause of the mitochondrial defects remains enigmatic. This review focuses on evidence to show that either event can lead to the evolution of the other with subsequent neuronal cell loss. Glutathione is a major antioxidant system used by cells and mitochondria for protection and is altered in a number of neurodegenerative and neuropathological conditions. This review also addresses the multiple roles for glutathione during mitochondrial inhibition or oxidative stress. Protein aggregation and inclusions are hallmarks of a number of neurodegenerative diseases. Recent evidence that links protein aggregation to oxidative stress and mitochondrial dysfunction will also be examined. Lastly, current therapies that target mitochondrial dysfunction or oxidative stress are discussed.

Animals↗

PubMed2005

Mitochondrial respiratory chain in brain homogenates: activities in different brain areas in patients with Alzheimer's disease.

BACKGROUND AND AIMS: The potential influence of impaired oxidative metabolism in the modulation of manifestations in sporadic Alzheimer's disease (AD) has attracted much attention in the last 50 years. Unfortunately, many clinical and experimental results aiming at proving this hypothesis are still controversial. The aim was to study the enzymatic activities of respiratory chain (RC) complexes I through V in three brain areas of a group of patients with definite AD, and to compare the results with a group of normal brains. We simultaneously assessed the lipid peroxidation of the samples as a measure of free radical damage. METHODS: The specific activity of the individual complexes of the RC was measured spectrophotometrically, and the loss of cis-parinaric acid fluorescence was used to determine the chemical process of lipid peroxidation. RESULTS: We were not able to detect differences in any of the analyzed RC enzymatic activities, or in the level of lipid peroxidation between patients with AD and controls. Instead, differences were found in the number of mitochondria and in the intrinsic enzymatic activities of complexes III and IV in various brain areas. CONCLUSIONS: Spectrophotometric enzymatic analyses of respiratory complexes in brain homogenates do not support the primary contribution of mitochondrial RC dysfunction in the pathogenesis of AD.

Aged↗

PubMed1983

Respiratory activities of subsarcolemmal and intermyofibrillar mitochondrial populations isolated from denervated and control rat soleus muscles.

Ultraturrax and Nagarse released populations of mitochondria isolated from control and day 21 denervated rat soleus muscle were characterized with respect to their oxidative phosphorylation, ADP translocase and ATPase activities. Both Ultraturrax and Nagarse released mitochondrial populations displayed lower capacities for oxidative phosphorylation; lower ADP translocase activities and higher Mg2+ stimulated ATPase activities than their corresponding controls. For both the denervated and control states, the Nagarse-released mitochondrial populations displayed significantly higher respiratory activities than the Ultraturrax released fractions. The significance of these findings is discussed with regard to the process of mitochondrial respiratory control. In addition the role of mitochondrial dysfunction in denervation muscular atrophy is assessed.

Adenosine Triphosphatases↗

PubMedDate not supplied

Placenta of idiopathic fetal growth restriction: cytochemically detectable enzyme activities do not change at a subcellular level.

The present study was designed to localize some important enzymes, such as adenosine diphospate-degrading enzyme (ADP-degrading enzyme) (plasma membrane enzyme), cytochrome c oxidase (mitochondrial enzyme) and glucose-6-phosphatase (endoplasmic reticulum enzyme), in placentae from patients with idiopathic fetal growth restriction (FGR) associated with absent end-diastolic flow velocity in the fetal umbilical artery. We compared these enzyme activities and their localization patterns to those in placentae both from pre-eclampsia with FGR and normal pregnancy with appropriate for their gestational age infants. In idiopathic FGR placentae, the intensity and localization patterns of these three enzymes did not differ from those seen in the placentae from normal pregnancy. Decreased ADP-degrading enzyme activity and cytochrome c oxidase negative mitochondria, which were characteristic features of pre-eclamptic trophoblasts, were absent from trophoblasts of the idiopathic FGR placentae. These observations indicated that enzyme-cytochemically detectable trophoblastic cell dysfunction may be absent in idiopathic FGR, or if present, there is less functional impairment of each trophoblast in this disease than in pre-eclampsia. Though both idiopathic FGR and pre-eclampsia lead to placental insufficiency, and finally to restricted fetal growth, a different mechanism and pathophysiology may work at the cellular and subcellular levels in these two diseases.

Adenosine Diphosphate↗

PubMed2001

Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations.

Four mitochondrial DNA (mtDNA) mutations at nps 3460, 11778, 14484, and 14459 account for roughly 90% of cases of Leber hereditary optic neuropathy (LHON) and are designated as "primary" LHON mutations since they act as major predisposition factors for LHON. Although each primary mutation can arise independently on different mtDNA backgrounds during human evolution, they characteristically do not co-occur in LHON patients. We report here a family with the simultaneous occurrence of the 11778A and 14484C mutations. Neuro-ophthalmological examination of the proband, a nine-year-old Caucasian female, revealed the bilateral optic atrophy, central scotomas, and reduced visual acuity typical of LHON. Her mother had normal appearing optic discs and is today visually asymptomatic. Analysis of the proband blood mtDNA revealed that she harbored both the 11778A (heteroplasmic, 94% mutant) and the 14484C (homoplasmic mutant) mutation. This genotype was maintained in proband lymphoblasts and transmitochondrial cybrids. The mother also had both mutations, with the 14484C mutation homoplasmic in all cell types examined. However, only 31% of her blood mtDNAs carried the 11778 mutation, which segregated to essentially 100% wild-type in lymphoblast and cybrid mtDNA. Complex I-linked respiration and specific enzyme activity were consistently lowest in proband lymphoblast and cybrid mitochondria compared to those from the mother, 11778A patients, 14484C patients, or controls, thus demonstrating both a deleterious synergistic interaction between the 11778A and 14484C mutations and the magnitude of 11778A-associated complex I dysfunction. Remarkably, spontaneous vision recovery occurred in the proband, highlighting the complexities encountered when associating mtDNA genotype and complex I function with LHON expression.

Cell Line↗

PubMed2005

Role of mitochondria in neuronal cell death induced by oxidative stress; neuroprotection by Coenzyme Q10.

Neuronal cells depend on mitochondrial oxidative phosphorylation for most of their energy needs and therefore are at a particular risk for oxidative stress. Mitochondria play an important role in energy production and oxidative stress-induced apoptosis. In the present study, we have demonstrated that external oxidative stress induces mitochondrial dysfunction leading to increased ROS generation and ultimately apoptotic cell death in neuronal cells. Furthermore, we have investigated the role of Coenzyme Q10 as a neuroprotective agent. Coenzyme Q10 is a component of the mitochondrial respiratory chain and a potent anti-oxidant. Our results indicate that total cellular ROS generation was inhibited by Coenzyme Q10. Further, pre-treatment with Coenzyme Q10 maintained mitochondrial membrane potential during oxidative stress and reduced the amount of mitochondrial ROS generation. Our study suggests that water-soluble Coenzyme Q10 acts by stabilizing the mitochondrial membrane when neuronal cells are subjected to oxidative stress. Therefore, Coenzyme Q10 has the potential to be used as a therapeutic intervention for neurodegenerative diseases.

Cell Death↗

PubMed1995

Leukotoxin, 9,10-epoxy-12-octadecenoate inhibits mitochondrial respiration of isolated perfused rat lung.

To investigate how mitochondrial function was affected in leukotoxin (Lx)-,9,10-epoxy-12-octadecenoate-induced lung injury, lung mitochondria were extracted from isolated perfused rat lung with or without Lx-induced edematous injury. In the lung treated with 30 mumol of Lx, the mitochondrial respiration rate in states 3 and 4 significantly decreased (without mitochondrial uncoupling) concomitantly with increased release of lactate dehydrogenase (LDH), a parameter for cellular damage, into the perfusate and decreased ATP content in the lung tissue compared with those of untreated lung. Moreover, 30 mumol of Lx resulted in significant inhibition of cytochrome-c oxidase activity (vs. vehicle control). In contrast, lower doses of Lx (10 mumol) caused lung edema and cellular damage without evidence for mitochondrial dysfunction. We also examined cellular and mitochondrial damage in hydrostatic lung edema. Such edema showed neither suppressed mitochondrial respiration nor elevated LDH activity in perfusate, although lung wet weight increased as much as it did after 30 mumol Lx treatment. Our results suggest that the ex vivo mitochondrial dysfunction is one of the secondary (vs. initial augmented permeability) but specific manifestations of toxicity of Lx, and together with the previous reports, the ex vivo damaging effect of Lx against mitochondria may be ascribed not to its direct action on mitochondria but to Lx-derived cellular mechanism(s).

Adenine Nucleotides↗

PubMed2004

Coupling the mitochondrial transcription machinery to human disease.

Mitochondria are the central processing units for cellular energy metabolism and, in addition to carrying out oxidative phosphorylation, regulate important processes such as apoptosis and calcium homeostasis. Because mitochondria possess a genome that is central to their multiple functions, an understanding of the mechanism of mitochondrial gene expression is required to decipher the many ways mitochondrial dysfunction contributes to human disease. Towards this end, two human transcription factors that are related to rRNA methyltransferases have recently been characterized, providing new insight into the mechanism of mitochondrial transcription and a novel link to maternally inherited deafness. Furthermore, studies in the Saccharomyces cerevisiae model system have revealed a functional coupling of transcription and translation at the inner mitochondrial membrane, where assembly of the oxidative phosphorylation system commences. Defects in an analogous coupling mechanism in humans might underlie the cytochrome oxidase deficiency that causes a form of Leigh Syndrome.

Animals↗

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↗

PubMed2006

Administration of levetiracetam after prolonged status epilepticus does not protect from mitochondrial dysfunction in a rodent model.

Neuronal death and dysfunction occur after status epilepticus (SE), and is associated with mitochondrial enzyme damage. We previously showed, using the rat perforant pathway stimulation model, that levetiracetam administration (LEV; 1000 mg/kg intraperitoneal) during established SE reduces seizure severity and prevents mitochondrial dysfunction. We now show that administration of the same dose of LEV after 5h SE, does not protect from mitochondrial dysfunction.

Animals↗

PubMed2001

Impaired retention of technetium-99m tetrofosmin in hypertrophic cardiomyopathy.

The purpose of this study was to determine whether myocardial imaging using technetium-99m tetrofosmin can noninvasively identify myocardial damage in hypertrophic cardiomyopathy (HC). The study consisted of 10 patients with apical HC, 10 with asymmetric septal HC (ASH) group, 5 with dilated cardiomyopathy (DC)-like group, and 20 healthy subjects. With use of a bull's-eye map of single-photon emission computed tomographic imaging, the total defect score of tetrofosmin and the washout rate were assessed in 5 segments (septum, and anterior, lateral, and inferior walls, and apex) of the left ventricle. A localized increase in defect score and washout rate was observed in the hypertrophied region in the group with apical HC. An increased washout rate was observed in the ASH group regardless of hypertrophy, suggesting that tetrofosmin retention by the mitochondria was impaired in the entire left ventricular wall. The washout rate was further increased at all segments in the DC-like group versus the ASH group. Tetrofosmin retention by mitochondria was impaired in the entire left ventricular wall in the ASH group and was increased further in the DC-like group. The dysfunction of myocardial cells was limited to the hypertrophied region in the apical HC group.

Cardiomyopathy, Dilated↗