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PubMed2004

Cd2+ versus Ca2+-produced mitochondrial membrane permeabilization: a proposed direct participation of respiratory complexes I and III.

A comparison of Cd2+ and Ca2+ effects on in vitro rat liver mitochondria function and a further study of their interaction were conducted. Similarity and distinction in action of rotenone, oligomycin, N-ethylmaleimide, dithiothreitol, catalase, dibucaine, ruthenium red, cyclosporin A (CsA), and ADP on Cd2+ and/or Ca2+-induced mitochondrial dysfunction were revealed. We found that rotenone exerted a strong protective action both against Ca2+ and Cd2+-produced mitochondrial membrane permeabilization (MMP). In contrast to Ca2+, catalase and dibucaine did not influence on main Cd2+ effects. In NH4NO3 medium N-ethylmaleimide (NEM) at low concentrations increased markedly Cd2+-produced swelling of non-energized mitochondria, whereas it exhibited a partial reversal effect following energization. In sucrose medium low [NEM] did not change Cd2+-produced mitochondrial swelling. High [NEM] promoted synergistic increase of the Cd2+-produced swelling in NH4NO3 medium; all above effects were reversed (and prevented) by dithiothreitol, DTT. We shown also that when exogenous Ca2+ and Pi were simultaneously present in NH4NO3 medium, DTT reversed only partially Cd2+-produced swelling of succinate plus rotenone-energized mitochondria, while DTT recovery action was complete when either Ca2+ or Pi were separately administered to the Cd2+-treated mitochondria. Besides, DTT added following a low Cd2+ pulse in KCl medium containing exogenous Ca2+ induced a substantial enhancing of sustained Cd2+ stimulation of mitochondrial basal respiration and the stimulation was CsA-sensitive, while the activation promoted by low [Cd2+] alone was totally eliminated by DTT supplement. We observed the similar respiratory activation earlier when high concentrations of Cd2+ in the absence of added Ca2+ were used but it was completely CsA-insensitive. A possible involvement of respiratory chain components, namely complex I (P-site) and complex III (S-site) in Cd2+ and/or Ca2+-produced MMP was discussed.

Adenosine Diphosphate↗
PubMed1998

Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells.

The bacterial alkaloid staurosporine is widely employed as an inducer of apoptosis in many cell types including neurons. The intracellular cascades that mediate staurosporine-induced apoptosis are largely unknown. Exposure of cultured PC12 cells to staurosporine resulted in a rapid (min) and prolonged (1-6 hr) elevation of intracellular free calcium levels [Ca2+]i, accumulation of mitochondrial reactive oxygen species (ROS), and decreased mitochondrial 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction (1-4 hr). These early events were followed by membrane lipid peroxidation, loss of mitochondrial transmembrane potential, and nuclear apoptotic changes. Treatment of cells with serum or nerve growth factor within 1-2 hr of staurosporine exposure resulted in recovery of [Ca2+]i and ROS levels, and rescued the cells from apoptosis. The increased [Ca2+]i and ROS production were required for staurosporine-induced apoptosis because the intracellular calcium chelator BAPTA and uric acid (an agent that scavenges peroxynitrite) each protected cells against apoptosis. The caspase inhibitor zVAD-fmk and the anti-apoptotic gene product Bcl-2 prevented the sustained [Ca2+]i increase and ROS accumulation induced by staurosporine indicating that caspases act very early in the apoptotic process. Our data indicate that a [Ca2+]i increase is an early and critical event in staurosporine-induced apoptosis that engages a cell death pathway involving ROS production, oxidative stress, and mitochondrial dysfunction.

Animals↗
PubMed2002

Does mitochondrial respiratory chain dysfunction have a role in common neurodegenerative disorders?

Respiratory chain dysfunction has been established as having a primary pathoaetiological role in certain relatively rare multisystem disorders (typically encephalomyopathies) and postulated as having an important role in commoner neurodegenerative disorders including Alzheimer dementia and Parkinson's disease. In the latter conditions, there is considerable evidence that non-mitochondrial factors have a key role in causation, making it unlikely that respiratory chain failure is the central event in pathoaetiology. Evidence is presented in this paper suggesting a role for mitochondrial dysfunction in upstream events predisposing to neurodegeneration, and in downstream events accelerating cell dysfunction and loss. While probably not having a primary role in pathoaetiology, respiratory chain dysfunction may still be an important risk factor for development of late life neurodegenerative disease and an important effector mechanism in neuronal dysfunction, and therefore represents a legitimate therapeutic target.

Aging↗
PubMed1989

Pre-eclampsia--a mitochondrial disease?

Mitochondrial dysfunction is a newly found group of inborn errors of metabolism in which there is a failure in the aerobic energy production. Disorders of mitochondrial metabolism exhibit a wide range of clinical symptoms which are related to the nature, severity and tissue distribution of the metabolic defect. Most reported cases are published in the neurological literature. In this report we describe for the first time a family with mitochondrial dysfunction with a high incidence of pre-eclampsia/eclampsia. The diagnosis of a mitochondrial disorder is verified by electronmicroscopic, electromyographic, histochemical and biochemical examinations. During pregnancy, the energy demand is increased due to both fetal and maternal requirements. A mitochondrial dysfunction, clinically symptomless in the non-pregnant state, may therefore become manifest during pregnancy. Characteristic features of pre-eclampsia such as disturbed ion transport, disturbed prostaglandin synthesis, vasoconstriction, platelet aggregation and hyperuricemia may be explained by mitochondrial dysfunction.

Adult↗
PubMed2005

Acrolein-induced cell death in PC12 cells: role of mitochondria-mediated oxidative stress.

Oxidative stress has been implicated in acrolein cytotoxicity in various cell types, including mammalian spinal cord tissue. In this study we report that acrolein also decreases PC12 cell viability in a reactive oxygen species (ROS)-dependent manner. Specifically, acrolein-induced cell death, mainly necrosis, is accompanied by the accumulation of cellular ROS. Elevating ROS scavengers can alleviate acrolein-induced cell death. Furthermore, we show that exposure to acrolein leads to mitochondrial dysfunction, denoted by the loss of mitochondrial transmembrane potential, reduction of cellular oxygen consumption, and decrease of ATP level. This raises the possibility that the cellular accumulation of ROS could result from the increased production of ROS in the mitochondria of PC12 cells as a result of exposure to acrolein. The acrolein-induced significant decrease of ATP production in mitochondria may also explain why necrosis, not apoptosis, is the dominant type of cell death. In conclusion, our data suggest that one possible mechanism of acrolein-induced cell death could be through mitochondria as its initial target. The subsequent increase of ROS then inflicts cell death and further worsens mitochondria function. Such mechanism may play an important role in CNS trauma and neurodegenerative diseases.

Acrolein↗
PubMed2005

Mitochondria-based model for fetal origin of adult disease and insulin resistance.

Insulin resistance has been recognized as the fundamental underlying metabolic defect in the pathogenesis of metabolic syndrome, a clustering of cardiovascular risk factors such as diabetes, hypertension, dyslipidemia, and obesity. Recent studies established that mitochondrial dysfunction is involved in insulin resistance in general and fetal origin of this state in particular. Because genes are the fundamental molecular basis of inheritance--and thus the cornerstones of evolution--a model explaining insulin resistance is based at the gene level at best. Since a certain mtDNA polymorphism, 16189T>C, is associated with insulin resistance, mtDNA has to be a basic component of the gene-based model. We developed a mitochondria-based model that explains insulin resistance in terms of quantitative and qualitative change of the mitochondrion and its DNA. This model can accommodate several important hypotheses, such as thrifty genotype hypothesis, thrifty phenotype hypothesis, fetal insulin hypothesis, contribution of metabolic imprinting by epigenetic changes, and many other features associated with insulin resistance. We will discuss mechanisms that indicate why the perturbed initial condition of mitochondrial function should lead to the reduced insulin sensitivity.

Aging↗
PubMed2002

Mitochondrial damage during ischemia determines post-ischemic contractile dysfunction in perfused rat heart.

Possible mechanisms underlying sodium overload-induced ischemia/reperfusion injury in perfused rat hearts were examined. Massive accumulation of myocardial Na(+) occurred during ischemia, suggesting cytosolic sodium overload in cardiac cells. Treatment of the pre-ischemic heart with 0.3 micromol/l tetrodotoxin or 3 micromol/l ethyl-isopropyl amiloride enhanced post-ischemic contractile recovery (72 or 82% of initial vs 24% for untreated group), which was associated with suppression of tissue Na(+) accumulation (138 or 141% of initial vs 270% for untreated group), restoration of tissue high-energy phosphates, and preservation of the ability of mitochondria to produce ATP in the ischemic/reperfused heart. The release of cytochrome c from the ischemic heart was observed, which was blocked by treatment of the pre-ischemic heart with these agents. The improvement of post-ischemic contractile recovery by these agents was closely correlated with the ability of mitochondria to produce ATP during ischemia. To examine the effects of sodium overload on mitochondrial function, isolated mitochondria were incubated in the presence of various concentrations of Na(+). Na(+) induced mitochondrial membrane perturbations such as depolarization of the membrane potential, mitochondrial swelling, cytochrome c release from isolated mitochondria, and a reduction in oxidative phosphorylation. These events in the isolated mitochondria were not blocked by the presence of the above agents. The results suggest that cytosolic sodium overload in cardiac cells may induce deterioration of the mitochondrial function during ischemia and that this mitochondrial damage may determine post-ischemic contractile dysfunction in perfused rat hearts.

Amiloride↗
PubMed1999

Rapid progression of cardiomyopathy in mitochondrial diabetes.

Cardiac involvement and its clinical course in a diabetic patient with a mitochondrial tRNA(Leu)(UUR) mutation at position 3243 is reported in a 54-year-old man with no history of hypertension. At age 46, an electrocardiogram showed just T wave abnormalities. At age 49, it fulfilled SV1 + RV5 or 6>35 mm with strain pattern. At age 52, echocardiography revealed definite left ventricular (LV) hypertrophy, and abnormally increased mitochondria were shown in biopsied endomyocardial specimens. He was diagnosed as having developed hypertrophic cardiomyopathy associated with the mutation. However, at age 54, SV1 and RV5,6 voltages were decreased, and echocardiography showed diffuse decreased LV wall motion and LV dilatation. Because he had mitochondrial diabetes, the patient's heart rapidly developed hypertrophic cardiomyopathy, and then it seemed to be changing to a dilated LV with systolic dysfunction. Rapid progression of cardiomyopathy can occur in mitochondrial diabetes.

Cardiomyopathy, Dilated↗
PubMed2004

Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease.

Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative activity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology.

Alzheimer Disease↗
PubMed2005

Mitochondrial dysfunction in cardiovascular disease.

Whereas the pathogenesis of atherosclerosis has been intensively studied and described, the underlying events that initiate cardiovascular disease are not yet fully understood. A substantial number of studies suggest that altered levels of oxidative and nitrosoxidative stress within the cardiovascular environment are essential in the development of cardiovascular disease; however, the impact of such changes on the subcellular or organellar components and their functions that are relevant to cardiovascular disease inception are less understood. In this regard, studies are beginning to show that mitochondria not only appear susceptible to damage mediated by increased oxidative and nitrosoxidative stress, but also play significant roles in the regulation of cardiovascular cell function. In addition, accumulating evidence suggests that a common theme among cardiovascular disease development and cardiovascular disease risk factors is increased mitochondrial damage and dysfunction. This review discusses aspects relating mitochondrial damage and function to cardiovascular disease risk factors and disease development.

Animals↗
PubMed1999

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

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

Adenosine Triphosphate↗
PubMed2006

New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics.

Cardiotoxic side-effects represent a serious complication of anticancer therapy with anthracyclines, in particular with doxorubicin (DXR) being the leading drug of the group. Different hypotheses, accentuating various mechanisms and/or targets, have been proposed to explain DXR-induced cardiotoxicity. This review focuses on the myocardial energetic network as a target of DXR toxic action in heart and highlights the recent advances in understanding its role in development of the DXR related cardiac dysfunction. We present a survey of DXR-induced defects in different steps of cardiac energy metabolism, including reduction of oxidative capacity of mitochondria, changes in the profile of energy substrate utilization, disturbance of energy transfer between sites of energy production and consumption, as well as defects in energy signaling. Considering the wide spectrum and diversity of the changes reported, we attempt to integrate these facts into a common framework and to discuss important functional and temporal relationships between DXR-induced events and the possible underlying molecular mechanisms.

AMP-Activated Protein Kinases↗
PubMed1989

Diagnosis and management of acute iron poisoning.

All children who ingest iron tablets accidentally are at risk of severe, possibly fatal, poisoning. Death in the first stage of acute iron poisoning is due to hypovolaemic shock; in the third stage it is due to widespread cellular dysfunction as a result of mitochondrial disruption caused by intracellular iron. It appears that once a critical amount of iron has reached the mitochondria therapy has little effect and the outcome is poor. Rational therapy must be started without delay. The crucial aspect of early management is to remove as much iron as possible from the intestine before absorption and tissue uptake can occur. The aims of parenteral chelation therapy are to prevent iron in the extracellular fluid from entering the cells and to protect the mitochondria from iron already in the cells. An effective circulating blood volume must be maintained. Iron poisoning occurs predominantly in areas where iron is given routinely to mothers during pregnancy without sufficient regard for its potentially lethal effects on toddlers. Child-proof packaging is the single most effective way to prevent iron poisoning but it is expensive and not practical in poor countries. Iron prophylaxis in pregnancy should be routine only in areas where a high prevalence of iron deficiency justifies it. It should be accompanied by education of the public, pharmacists, nurses and doctors.

Chelating Agents↗
PubMed2003

Nucleoside analogues and neuropathy in the era of HAART.

BACKGROUND: Sensory neuropathies occur commonly in the setting of HIV infection. Sensory neuropathy (SN) is clearly associated with HIV itself, and in this context develops in association with increased macrophage activation in the peripheral nervous system. A clinically identical SN may also occur as a consequence of exposure to some HIV treatments. In this setting, impaired mitochondrial function is thought to play a role in the development of neurological dysfunction. OBJECTIVE: This review explores the evidence for the neurotoxicity of HIV and HIV treatments, the effect of nucleoside reverse transcriptase inhibitors on mitochondria, and the likely associations between these. CONCLUSIONS: Dideoxynucleotide drugs are commonly associated with SN. The nucleoside reverse transcriptase inhibitors inhibit mitochondrial DNA synthesis and may thus exacerbate existing viral-induced nerve damage.

Animals↗
PubMed2002

Frataxin deficiency and mitochondrial dysfunction.

Friedreich ataxia (FA) is an inherited recessive disorder characterized by progressive neurological disability and heart abnormalities. The Friedreich ataxia gene (FRDA) encodes a small mitochondrial protein, frataxin, which is produced in insufficient amounts in the disease as a consequence of a GAA triplet repeat expansion in the first intron of the gene. Frataxin deficiency leads to excessive free radical production, dysfunction of Fe-S center containing enzymes (in particular respiratory complexes I, II and III, and aconitase), and progressive iron accumulation in mitochondria. Frataxin may be a mitochondrial iron-binding protein that prevents this metal from participating in Fenton chemistry to generate toxic hydroxyl radicals. We investigated whether frataxin deficiency may in addition interfere with signaling pathways. First, we showed that exposure of FA fibroblasts to iron fails to produce the normally observed increase in expression of the stress defense protein manganese superoxide dismutase. This impaired induction involves a nuclear factor-kappaB-independent pathway that does not require free radical signaling intermediates. We also examined the role of frataxin in neuronal differentiation by using stably transfected clones of P19 embryonic carcinoma cells with antisense or sense frataxin constructs. We found that during retinoic acid-induced neurogenesis frataxin deficiency enhances apoptosis and reduces the number of terminally differentiated neuronal-like cells. The addition of the antioxidant N-acetyl-cysteine only rescues cells non-committed to the neuronal lineage, indicating that frataxin deficiency impairs differentiation mechanisms and survival responses through different mechanisms. Both studies suggest that some abnormalities in frataxin-deficient cells are related to free radical independent signaling pathways.

Journal Article↗
PubMedDate not supplied

Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders.

When subjected to excessive oxidative stress, neurons may respond adaptively to overcome the stress, or they may activate a programmed cell death pathway called apoptosis. Apoptosis is characterized by alterations in mitochondria and the endoplasmic reticulum and activation of cysteine proteases called caspases. Increasing evidence suggests that apoptotic biochemical cascades are involved in the dysfunction and death of neurons in neurodegenerative disorders such as Alzheimer's, Parkinson, and Huntington's diseases. Studies of normal aging, of genetic mutations that cause disease, and of environmental factors that affect disease risk are revealing cellular and molecular alterations that may cause excessive oxidative stress and trigger neuronal apoptosis. Accumulation of self-aggregating proteins such as amyloid beta-peptide, tau, alpha-synuclein, and huntingtin may be involved in apoptosis both upstream and downstream of oxidative stress. Membrane-associated oxidative stress resulting in perturbed lipid metabolism and disruption of cellular calcium homeostasis may trigger apoptosis in several different neurodegenerative disorders. Counteracting neurodegenerative processes are an array of mechanisms including neurotrophic factor signaling, antioxidant enzymes, protein chaperones, antiapoptotic proteins, and ionostatic systems. Emerging findings suggest that the resistance of neurons to death during aging can be enhanced by modifications of diet and lifestyle.

Animals↗
PubMed2001

Ischemic preconditioning preserves mitochondrial function after global cerebral ischemia in rat hippocampus.

Ischemic tolerance in brain develops when sublethal ischemic insults occur before "lethal" cerebral ischemia. Two windows for the induction of tolerance by ischemic preconditioning (IPC) have been proposed: one that occurs within 1 hour after IPC, and another that occurs 1 or 2 days after IPC. The authors tested the hypotheses that IPC would reduce or prevent ischemia-induced mitochondrial dysfunction. IPC and ischemia were produced by bilateral carotid occlusions and systemic hypotension (50 mm Hg) for 2 and 10 minutes, respectively. Nonsynaptosomal mitochondria were harvested 24 hours after the 10-minute "test" ischemic insult. No significant changes were observed in the oxygen consumption rates and activities for hippocampal mitochondrial complexes I to IV between the IPC and sham groups. Twenty-four hours of reperfusion after 10 minutes of global ischemia (without IPC) promoted significant decreases in the oxygen consumption rates in presence of substrates for complexes I and II compared with the IPC and sham groups. These data suggest that IPC protects the integrity of mitochondrial oxidative phosphorylation after cerebral ischemia.

Animals↗