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PubMedDate not supplied

Age-associated changes in oxidative damage and the activity of antioxidant enzymes in rats with inherited overgeneration of free radicals.

Reactive oxygen species have been hypothesized to play an important role in the process of aging. To investigate the correlation between oxidative stress and accumulation of protein and DNA damage, we have compared the age-dependent levels of protein carbonyl groups and the activities of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase in cytosol and mitochondrial extracts from liver cells of Wistar and OXYS rats. The latter strain is characterized by increased sensitivity to free radicals. Faster age-dependent increase in the level of protein carbonyl groups was found in OXYS as compared with Wistar rats. A complicated enzyme-specific pattern of age-dependent changes in the activities of antioxidant enzymes was observed. Long-term uptake of dietary supplements Mirtilene forte (extract from the fruits of Vaccinium myrtillus L.) or Adrusen zinco (vitamin E complex with zinc, copper, selenium and omega-3 polyunsaturated fatty acids) sharply decreased the level of protein oxidation in cytosol and mitochondrial extracts of hepatocytes of Wistar and of OXYS rats. Both dietary supplements increased the activity of catalase in the liver mitochondria of OXYS rats. Our results are in agreement with the shorter life-span of OXYS and with the mitochondrial theory of aging, which postulates that accumulation of DNA and protein lesions leads to mitochondrial dysfunction and accelerates the process of aging.

Aging↗

PubMed1995

Mitochondrial dysfunction in adult-onset myopathies with structural abnormalities.

Three patients with chronic progressive external ophthalmoplegia of adult-onset, generalized muscle atrophy and myalgia are described. Two patients fulfilled the histological criteria for centronuclear myopathy, the third those for fiber-type disproportion. Additionally, typical ragged red fibers were found in all muscle specimens, and several muscle fibers were cytochrome c oxidase negative. NADH and succinate dehydrogenase stains showed increased subsarcolemmal accumulation of mitochondria. To determine whether these findings are coincidental or whether they indicated an additional mitochondrial disorder, all patients were investigated using biochemical analysis of the respiratory chain, molecular genetics, magnetic resonance spectroscopy of quadriceps muscle and ergometry. These tests suggested an additional mitochondrial dysfunction. Mitochondrial dysfunction seems to be more common in this group of myopathies than previously estimated, and may be of importance in the pathogenesis of these disorders.

Adult↗

PubMed1998

Decline in the expression of copper/zinc superoxide dismutase in the kidney of rats with endotoxic shock: effects of the superoxide anion radical scavenger, tempol, on organ injury.

1. Endotoxaemia causes an enhanced formation of reactive oxygen species (ROS) which contribute to the multiple organ dysfunction syndrome (MODS) in septic shock. Here we investigate (i) the effects of endotoxin on the expression of two isoforms of superoxide dismutase (SOD), namely Cu/Zn-SOD (cytosol) and Mn-SOD (mitochondria) in the rat kidney, and (ii) the effects of the radical scavenger tempol on the MODS caused by lipopolysaccharide (LPS, E. coli, 6 mg kg(-1) i.v.) in the rat. 2. Endotoxaemia resulted in a rapid, but transient, decline in the expression of both mRNA and protein of Cu/Zn-SOD as well as an increase in the expression of the mRNA of Mn-SOD in the kidney. Endotoxaemia for 6 h also caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of nitrite/nitrate. 3. Pretreatment of rats with tempol (100 mg kg(-1) i.v. bolus injection, 15 min prior to LPS followed by an infusion of 30 mg kg(-1) i.v., n=9) did not affect the circulatory failure, but attenuated the renal dysfunction and the hepatocellular injury/dysfunction caused by LPS. Tempol did not affect the rise in nitrite/nitrate caused by endotoxin. 4. These results imply that an enhanced formation of ROS (including superoxide anions) in conjunction with inadequate defences against such ROS contributes to the injury and dysfunction of the kidney and the liver in endotoxic shock.

Animals↗

PubMed1985

Fatal infantile mitochondrial myopathy and renal dysfunction caused by cytochrome c oxidase deficiency: immunological studies in a new patient.

A 3-month-old female infant had profound generalized weakness, de Toni-Fanconi-Debre syndrome, and lactic acidosis. She required assisted ventilation and died at the age of 8 months. Muscle biopsy showed accumulation of mitochondria, glycogen, and lipid droplets. Histochemical reaction and immunocytochemical stain for cytochrome c oxidase showed very weak results, but both reactions were normal in intrafusal fibers of the muscle spindle. In crude extracts of the patient's muscle, cytochrome c oxidase activity was undetectable and enzyme-linked immunosorbent assay showed decreased reaction at all dilutions of antiserum. These data indicate that the amount of immunoreactive enzyme protein is markedly decreased in muscle of patients with fatal infantile cytochrome c oxidase deficiency and renal dysfunction.

Biopsy↗

PubMed2003

Mitochondria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae.

Using Saccharomyces cerevisiae as a model organism, we analyzed the consequences of disrupting mitochondrial function on mutagenesis of the nuclear genome. We measured the frequency of canavanine-resistant colonies as a measure of nuclear mutator phenotype. Our data suggest that mitochondrial dysfunction leads to a nuclear mutator phenotype (i) when oxidative phosphorylation is blocked in wild-type yeast at mitochondrial complex III by antimycin A and (ii) in mutant strains lacking the entire mitochondrial genome (rho(0)) or those with deleted mitochondrial DNA (rho(-)). The nuclear mutation frequencies obtained for antimycin A-treated cells as well as for rho(-) and rho(0) cells were approximately 2- to 3-fold higher compared to untreated control and wild-type cells, respectively. Blockage of oxidative phosphorylation by antimycin A treatment led to increased intracellular levels of reactive oxygen species (ROS). In contrast, inactivation of mitochondrial activity (rho(-) and rho(0)) led to decreased intracellular levels of ROS. We also demonstrate that in rho(0) cells the REV1, REV3 and REV7 gene products, all implicated in error-prone translesion DNA synthesis (TLS), mediate mutagenesis in the nuclear genome. However, TLS was not involved in nuclear DNA mutagenesis caused by inhibition of mitochondrial function by antimycin A. Together, our data suggest that mitochondrial dysfunction is mutagenic and multiple pathways are involved in this nuclear mutator phenotype.

Antimycin A↗

PubMed2004

Cell-penetrating peptides do not cross mitochondrial membranes even when conjugated to a lipophilic cation: evidence against direct passage through phospholipid bilayers.

CPPs (cell-penetrating peptides) facilitate the cellular uptake of covalently attached oligonucleotides, proteins and other macromolecules, but the mechanism of their uptake is disputed. Two models are proposed: direct movement through the phospholipid bilayer and endocytic uptake. Mitochondria are a good model system to distinguish between these possibilities, since they have no vesicular transport systems. Furthermore, CPP-mediated delivery of macromolecules to the mitochondrial matrix would be a significant breakthrough in the study of mitochondrial function and dysfunction, and could also lead to new therapies for diseases caused by mitochondrial damage. Therefore we investigated whether two CPPs, penetratin and Tat, could act as mitochondrial delivery vectors. We also determined whether conjugation of the lipophilic cation TPP (triphenylphosphonium) to penetratin or Tat facilitated their uptake into mitochondria, since TPP leads to uptake of attached molecules into mitochondria driven by the membrane potential. Neither penetratin nor Tat, nor their TPP conjugates, are internalized by isolated mitochondria, indicating that these CPPs cannot cross mitochondrial phospholipid bilayers. Tat and TPP-Tat are taken up by cells, but they accumulate in endosomes and do not reach mitochondria. We conclude that CPPs cannot cross mitochondrial phospholipid bilayers, and therefore cannot deliver macromolecules directly to mitochondria. Our findings shed light on the mechanism of uptake of CPPs by cells. The lack of direct movement of CPPs through mitochondrial phospholipid bilayers, along with the observed endosomal accumulation of Tat and TPP-Tat in cells, makes it unlikely that CPPs enter cells by direct membrane passage, and instead favours cellular uptake via an endocytic pathway.

Amino Acid Sequence↗

PubMed2003

Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia.

Ischemia/reperfusion of heart causes contractile dysfunction, necrosis and/or apoptosis and is a major cause of human death, but the molecular mechanisms are unclear. We show that ischemia alone (without reperfusion) is sufficient to induce apoptosis and mitochondrial dysfunction, and we have investigated the mechanism responsible; 30 and 60 min stop-flow ischemia in Langendorff-perfused rat hearts induced progressive (a). release of cytochrome c from mitochondria to cytosol, (b). inhibition of the mitochondrial respiratory functions, (c). activation of caspase-3-like protease activity and (d). DNA strand breaks (however, only 2% of myocyte nuclei were TUNEL positive at 60 min). Fifteen minutes pre-perfusion of hearts with cyclosporin A, an inhibitor of mitochondrial-permeability transition (MPT), largely prevented all these ischemic changes. Pre-perfusion of hearts with FK506, an inhibitor of calcineurin, caused no protection. Pre-perfusion with DEVD-CHO, an inhibitor of caspase-3-like proteases, completely prevented ischemia-induced DNA strand breaks, but only partially blocked cytochrome c release and mitochondrial respiratory inhibition. Reperfusion of hearts after 30 min ischemia further stimulated caspase activity and nuclear apoptosis. We conclude that ischemia-induced MPT causes release of cytochrome c, which then activates the caspases that execute apoptosis and feedback to cause further cytochrome c release. The MPT-induced cytochrome c release is also largely responsible for the ischemic respiratory inhibition, which might contribute to contractile dysfunction or necrosis at reperfusion.

Animals↗

PubMedDate not supplied

Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death?

Experimental traumatic brain injury (TBI) and spinal cord injury (SCI) result in a rapid and significant necrosis of neuronal tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the primary damage, resulting in significant neurologic dysfunction. It is believed that alterations in excitatory amino acids (EAA), increased reactive oxygen species (ROS), and the disruption of Ca(2+) homeostasis are major factors contributing to the ensuing neuropathology. Mitochondria serve as the powerhouse of the cell by maintaining ratios of ATP:ADP that thermodynamically favor the hydrolysis of ATP to ADP + P(i), yet a byproduct of this process is the generation of ROS. Proton-pumping by components of the electron transport system (ETS) generates a membrane potential (DeltaPsi) that can then be used to phosphorylate ADP or sequester Ca(2+) out of the cytosol into the mitochondrial matrix. This allows mitochondria to act as cellular Ca(2+) sinks and to be in phase with changes in cytosolic Ca(2+) levels. Under extreme loads of Ca(2+), however, opening of the mitochondrial permeability transition pore (mPTP) results in the extrusion of mitochondrial Ca(2+) and other high- and low-molecular weight components. This catastrophic event discharges DeltaPsi and uncouples the ETS from ATP production. Cyclosporin A (CsA), a potent immunosuppressive drug, inhibits mitochondrial permeability transition (mPT) by binding to matrix cyclophilin D and blocking its binding to the adenine nucleotide translocator. Peripherally administered CsA attenuates mitochondrial dysfunction and neuronal damage in an experimental rodent model of TBI, in a dose-dependent manner. The underlying mechanism of neuroprotection afforded by CsA is most likely via interaction with the mPTP because the immunosuppressant FK506, which has no effect on the mPT, was not neuroprotective. When CsA was administrated after experimental SCI at the same dosage and regimen used TBI paradigms, however, it had no beneficial neuroprotective effects. This review takes a comprehensive and critical look at the evidence supporting the role for mPT in central nervous system (CNS) trauma and highlights the differential responses of CNS mitochondria to mPT induction and the implications this has for therapeutically targeting the mPT in TBI and SCI.

Animals↗

PubMedDate not supplied

Role of mitochondrial deterioration in physiological and pathological brain aging.

BACKGROUND: Mitochondria are widely reported to occupy a unique role in modulating cell viability, senescence and death. This is consistently supported by the multiple functions of these organelles. In addition to providing the energy for the myriad of cellular performances, mitochondria are involved in regulating thermogenesis, calcium buffering, integration of pro- and anti-apoptotic signals. OBJECTIVE: To stress the significant importance of subtle, continuous and permanent mitochondrial alterations as key events in physiological aging and as unfavourable determinants of age-related neurodegenerative diseases. RESULTS: Any dysfunction of these organelles may constitute a serious threat for cellular health status and survival, particularly of post-mitotic nerve and muscle cells. Mitochondrial deterioration may affect discrete features of the organelles (such as their structural dynamics, genetics and physiology) and lead to a progressive functional impairment. CONCLUSIONS: A variety of mitochondrial tasks, while hampering the possibility to recover the organelles' dysfunctions, offer different and reliable opportunities for therapeutic interventions.

Aging↗

PubMed1993

Growth factors prevent mitochondrial dysfunction, loss of calcium homeostasis, and cell injury, but not ATP depletion in hippocampal neurons deprived of glucose.

The mechanism of growth factor protection against metabolic/excitotoxic insults was examined. The time course of changes in ATP levels, mitochondrial transmembrane potential, intracellular free calcium levels ([Ca2+]i), and cell survival resulting from glucose deprivation were assessed in cultured hippocampal neurons. ATP levels were significantly reduced within 1 h of the onset of glucose deprivation and reached less than 20% of control levels by 12 h. Mitochondrial transmembrane potential (assessed by rhodamine 123 accumulation in mitochondria) declined progressively between 4 and 20 h following the onset of glucose deprivation. The [Ca2+]i was reduced during the first 1 h of glucose deprivation, gradually rose through 12 h, and then rose rapidly and was elevated five- to sevenfold after 16 h. The [Ca2+]i did not increase, and mitochondrial dysfunction and cell damage were prevented, in hypoglycemic neurons incubated in Ca(2+)-deficient medium. Elevation of [Ca2+]i by exposure of neurons to glutamate caused loss of rhodamine 123 fluorescence and structural damage to mitochondria. Mitochondrial function could be restored and cell survival maintained by addition of glucose prior to the late elevation of [Ca2+]i. Nerve growth factor (NGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor II (IGF-II) prevented loss of both [Ca2+]i homeostasis and mitochondrial transmembrane potential, and protected hippocampal neurons against hypoglycemic injury, but did not prevent the hypoglycemia-induced reduction in ATP levels. NaCN and 2,4-dinitrophenol (DNP) caused a large elevation of [Ca2+]i, mitochondrial dysfunction, and cell death. NGF, bFGF, and IGF-II each significantly reduced the adverse effects of NaCN and DNP on [Ca2+]i, mitochondrial function, and cell survival. Loss of [Ca2+]i homeostasis may be a critical event leading to mitochondrial damage and cell death resulting from energy failure. Preventing loss of [Ca2+]i homeostasis may be a general mechanism for the neuroprotective action of growth factors.

Adenosine Triphosphate↗

PubMed2000

Drug delivery to mitochondria: the key to mitochondrial medicine.

The major function of mitochondria in human cells is to provide ATP by oxidative phosphorylation. However, mitochondria have many other roles including the modulation of intracellular calcium concentration and the regulation of apoptotic cell death. Furthermore, the mitochondrial respiratory chain is a major source of damaging free radicals. Consequently, mitochondrial dysfunction contributes to a number of human diseases, ranging from neurodegenerative diseases and ischaemia-reperfusion injury to obesity and diabetes. In addition, mutations to nuclear or mitochondrial DNA cause a number of human diseases. Therefore, strategies to prevent mitochondrial damage or to manipulate mitochondrial function in clinically useful ways may provide new therapies for a range of human disorders. Here we outline why mitochondria are a potentially important target for drug delivery and discuss how to deliver bioactive molecules selectively to mitochondria within cells.

Animals↗

PubMed2005

Mitochondrial disorders in chagasic cardiomyopathy.

The mitochondria play a complex multi-factorial role in the cell. Along with their primary role in energy (ATP) production, mitochondria generate reactive oxygen species (ROS) that directly or indirectly affect several cellular functions. In this article, I review the molecular, structural and functional mitochondrial abnormalities reported in chagasic cardiomyopathy. I highlight current information about the potential etiology and the pathophysiological significance of mitochondrial dysfunction in chagasic cardiomyopathy and provide a brief background of mitochondrial biogenesis and bioenergetic pathways in cardiac growth and development.

Chagas Cardiomyopathy↗

PubMed2003

Mitochondrial dysfunction in CD47-mediated caspase-independent cell death: ROS production in the absence of cytochrome c and AIF release.

Ligation of CD47 by its natural ligand thrombospondin (TSP), or cross-linking by CD47 antibodies, triggers caspase-independent cell death in normal and leukemic cells. This kind of cell death is characterised by the cytoplasmic events of apoptosis including externalisation of phosphatidylserines and mitochondria swelling. We report herein selective mitochondrial changes in CD47-dependent cell death of T cells. After T cell stimulation via CD47, a rapid mitochondrial transmembrane potential (deltapsi(m)) disruption is accompanied by the production of reactive oxygen species (ROS) and phosphatidylserine exposure. Surprisingly, mitochondrial dysfunction does not induce cytochrome c or AIF release. Moreover, the dying cells do not exhibit caspase-3 activation and display intact nuclei without any large-scale, or oligonucleosomal DNA fragmentation. We conclude that DeltaPsi(m) loss and ROS production are an early step in CD47-dependent killing and neither cytochrome c, nor AIF are implicated in this new cell death pathway.

Antibodies, Monoclonal↗

PubMed1989

Renal cortical mitochondrial integrity in experimental cyclosporine nephrotoxicity.

The function of renal cortical mitochondria isolated from rats with cyclosporine nephrotoxicity was studied. Renal cortical mitochondria were isolated from 5 male Fischer rats after 14 days of daily intraperitoneal administration of CsA, 25 mg/kg body wt. Compared with the mitochondrial function of 5 pair-fed control rats receiving vehicle alone, state 3 respiration (ADP-dependent) using several substrates was mildly depressed only with pyruvate-malate supported respiration (27 +/- 3 vs. 36 +/- 2 nmol O2/min/mg protein; P less than 0.05). The Ca2+ accumulation rate was slightly reduced (354 +/- 14 vs. 416 +/- 18 nmol/min/mg protein; P less than 0.025) while the cytochrome enzyme concentrations were not different from controls. Respiratory control ratios were not affected (CsA group: 9.5 +/- 2.8, control group: 8.9 +/- 2.3; glutamate-malate as substrates). These minor alterations in mitochondrial function occurred in the presence of severe depression in the glomerular filtration rate and renal morphologic changes commonly seen with CsA administration. Moreover, there was no increase in enzymuria. These results indicate that CsA has minor effects on the respiratory function of renal cortical mitochondria. The severe depression in the glomerular filtration rate is out of proportion to these minor alterations in mitochondrial function. These findings argue against a prominent role for a direct toxic action of CsA on tubular cells in the pathogenesis of acute cyclosporine-induced renal dysfunction.

Animals↗

PubMed2001

Intestinal mitochondrial dysfunction in surgical stress.

BACKGROUND: Surgical stress is associated with altered intestinal function. Our earlier study using a rat model indicated that oxidative stress plays an important role in this process. Since mitochondria are crucial to cellular function and survival and are both a target as well as a source of reactive oxygen species, the present study looks at the changes in enterocyte mitochondria during surgical stress. METHODS: Surgical stress was induced by opening the abdominal wall and handling the intestine as done during laparotomy. Mitochondria were prepared from the isolated enterocytes at different time periods after surgical stress. The effect of surgical stress on enterocyte mitochondrial ultrastructure, respiration, anti-oxidant enzyme activity, thiol redox status, calcium flux, permeability, and matrix enzymes was then studied. RESULTS: Surgical stress resulted in alterations in mitochondrial respiration and thiol redox status. It was also associated with altered mitochondrial matrix enzyme activity, decreased superoxide dismutase activity, induction of mitochondrial permeability transition, and swelling, as well as impairment of mitochondrial calcium flux. These alterations were seen at a maximum of 60 min following surgical stress and were reversed by 24 h. CONCLUSIONS: Laparotomy and mild intestinal handling itself results in enterocyte mitochondrial damage. Since mitochondria are important cellular organelles, this damage can probably lead to compromised intestinal function.

Animals↗

PubMedDate not supplied

Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus.

Activation, proliferation, or programmed cell death of T lymphocytes are dependent on controlled reactive oxygen intermediates (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (Delta Psi(m)) also plays a decisive role in cell survival by controlling activity of redox-sensitive caspases. T lymphocytes of patients with systemic lupus erythematosus (SLE) exhibit mitochondrial hyperpolarization, increased ROI production, diminished intracellular glutathione levels, cytoplasmic alkalinization, and ATP depletion that mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. These redox and metabolic checkpoints represent novel targets for pharmacological intervention in SLE.

Adenosine Triphosphate↗

PubMed1990

Halothane impairs the bioenergetic functions of isolated rat liver mitochondria.

The effect of halothane, a potent and popular volatile anesthetic, on isolated rat liver mitochondria was examined. Halothane inhibited state 3 and dinitrophenol-induced uncoupled respiration with NAD(+)-linked substrates, but not with FAD-linked substrates, and did not affect the oxidation-reduction state of mitochondrial cytochromes. Moreover, halothane increased state 4 respiration and ATPase activity and decreased the extra-mitochrondrial pH change coupled to ATP synthesis. These results indicate that halothane impairs mitochondrial ATP production by interfering with both the electron transport from NAD+ to FAD and the coupling of oxidative phosphorylation. Halothane only slightly affected the membrane potential, which is commonly dissipated by typical classical uncouplers. Moreover, halothane inhibited both ATP-driven and respiration-driven Ca2+ accumulation in mitochondria and stimulated Ca2+ release from mitochondrial stores at concentrations higher than those at which it inhibited ATP production. These findings indicate that the uncoupling action of halothane is not classical. During halothane anesthesia, these mitochondrial abnormalities may contribute to hepatocyte dysfunctions.

Adenosine Triphosphatases↗

PubMed1983

Calcific diseases. A concept.

New observations portray calcification processes as similar whether occurring normally or pathologically. Most forms of calcification are initiated by membranous organelles, ie, extracellular, calcifying "matrix vesicles" or intracellular mitochondria. Matrix vesicles promote calcification through calcium-binding phospholipids and phosphatase activity. Mitochondria use a forceful, inwardly directed Ca and phosphate transport mechanism. After mineral initiation, the proliferation of mineral crystals is dependent on regulatory factors, such as extracellular Ca2+ and PO4(3-) and other mineral inhibitors and promoters. Calcific diseases are defined as those in which (1) Ca uptake is early, (2) calcification is importantly related to dysfunction, and (3) the control of calcification may lead to decreased morbidity or enhanced diagnostic capability. Calcific diseases include such well-known entities as crystal deposition arthritis, atherosclerosis, calcific valvular sclerosis, tumor calcification, dental plaque, and dysfunctional calcification occurring in implanted cardiovascular devices.

Arteriosclerosis↗