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PubMed2004

Oocyte mitochondria: strategies to improve embryogenesis.

Mitochondria play a central role to provide ATP for fertilization and preimplantation embryo development in the ooplasm. The mitochondrial dysfunction of oocyte has been proposed as one of the causes of high levels of developmental retardation and arrest that occur in preimplantation embryos generated using Assisted Reproductive Technology. Cytoplasmic transfer (CT) from a donor to a recipient oocyte has been applied to infertility due to dysfunctional ooplasm, with resulting pregnancies and births. However, neither the efficacy nor safety of this procedure has been appropriately investigated. In order to improve embryogenesis, we observed the mitochondrial distribution in ooplasma under the several conditions using mitochondrial GFP-transgenic mice (mtGFP-tg mice) in which the mitochondria are visualized by GFP. In this report, we will present our research about the mitochondrial distribution in ooplasm during early embryogenesis and the fate of injected donor mitochondria after CT using mtGFP-tg mice. The mitochondria in ooplasm from the germinal vesicle stage to the morula stage were accumulated in the perinuclear region. The mitochondria of the mtGFP-tg mouse oocyte transferred into the wild type mouse embryo could be observed until the blastocysts stage, suggesting that the mtGFP-tg mice oocyte is very useful for visual observation of the mitochondrial distribution in the oocyte, and that the aberrant early developmental competences due to the oocyte mitochondrial dysfunction may be overcome by transferring the "normal" mitochondria.

Animals↗

PubMed2005

Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition.

Mitochondria have been suggested to be causally linked to age-related alterations through respiratory chain dysfunction and formation of reactive oxygen species, leading to damage of mitochondrial DNA. Impaired biosynthesis of respiratory chain and ATP synthase subunits encoded by mitochondrial genes would set up a vicious cycle contributing to the aging process. Mitochondria are also involved in the increased susceptibility to ischemic injury observed in aged hearts, a process where the mitochondrial permeability transition pore (PTP) may play a role. Here, we analyze (i) the possible mechanisms through which PTP opening might contribute to age-related myocardial alterations; (ii) the available evidence of an increased probability of PTP opening in mitochondria isolated from aged tissues; (iii) the current methodological limitations that complicate the elucidation of causal relationships between PTP opening, mitochondrial dysfunction, and myocardial aging.

Aging↗

PubMed2004

Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family.

Hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome is caused by mutations in the SLC25A15 (ORNT1) gene encoding the mitochondrial ornithine transporter, but the mechanism of pathogenesis of the encephalopathy, spastic paraparesis and hepatopathy remains undetermined. HHH syndrome was diagnosed in a 2-year-old Palestinian boy with developmental delay and seizures, and subsequently in his 13-year-old brother with developmental delay. Direct sequencing of the PCR products of SLC25A15 exon amplifications revealed that both brothers were homozygous for a novel 446G deletion in exon 3 as well as for a 760A>T (I254L) polymorphism in exon 5, which is downstream of a premature termination codon produced by the frameshift resulting from the 446G deletion. The index patient had elevated liver enzymes as well as hyperalaninemia, lactic acidemia with an elevated lactate to pyruvate ratio, and increased urinary excretion of lactate, glutarate and Krebs cycle intermediates. These findings are indicative of mitochondrial dysfunction and are in accordance with ultrastructural studies showing increased numbers of large and bizarre mitochondria in liver, muscle, leukocytes and fibroblasts of some HHH patients. Neurologic and hepatic manifestations are characteristic of some primary mitochondrial disorders. Secondary mitochondrial dysfunction may contribute to the pathogenesis of these same features in HHH syndrome.

Adolescent↗

PubMed2001

Mitochondrial modulation of calcium signaling at the initiation of development.

Fertilization triggers cytosolic Ca(2+) oscillations that activate mammalian eggs and initiate development. Extensive evidence demonstrates that Ca(2+) is released from endoplasmic reticulum stores; however, less is known about how the increased Ca(2+) is restored to its resting level, forming the Ca(2+) oscillations. We investigated whether mitochondria also play a role in activation-associated Ca(2+) signaling. Mitochondrial dysfunction induced by the mitochondrial uncoupler FCCP or antimycin A disrupted cytosolic Ca(2+) oscillations, resulting in sustained increase in cytosolic Ca(2+), followed by apoptotic cell death. This suggests that functional mitochondria may participate in sequestering the released Ca(2+), contributing to cytosolic Ca(2+) oscillations and preventing cell death. By centrifugation, mouse eggs were stratified and separated into fractions containing both endoplasmic reticulum and mitochondria and fractions containing endoplasmic reticulum with no mitochondria. The former showed Ca(2+) oscillations by activation, whereas the latter exhibited sustained elevation in cytosolic Ca(2+) but no Ca(2+) oscillations, suggesting that mitochondria take up released cytosolic Ca(2+). Further, using Rhod-2 for detection of mitochondrial Ca(2+), we found that mitochondria exhibited Ca(2+) oscillations, the frequency of which was not different from that of cytosolic Ca(2+) oscillations, indicating that mitochondria are involved in Ca(2+) signaling during egg activation. Therefore, we propose that mitochondria play a crucial role in Ca(2+) signaling that mediates egg activation and development, and apoptotic cell death.

Animals↗

PubMed1997

Oxidant-mediated repression of mitochondrial transcription in diabetic rats.

Diabetes-associated mitochondrial dysfunction is recognized, but the underlying mechanisms are unknown. Using isolated liver mitochondria from streptozotocin-induced diabetic Sprague-Dawley rats, we showed that diabetes can result in a > 95% loss in mitochondrial transcriptional capacity. Decreased transcription correlated well with both disease status, as indicated by serum lipemia and ketone levels, and with increased resistance of the mitochondrial transcription system to oxidative stress imposed by the hydrophilic AAPH [2,2'-azobis-(2-amidino-propane) hydrochloride] or the hydrophobic AMVN [2,2'-azobis-(2,4,-dimethyl-valeronitrile)]. The onset of AAPH- or AMVN-induced lipid peroxidation was also delayed; this suggests that liver mitochondrial membranes from diabetics have increased resistance to peroxyl radical-mediated lipid peroxidation. Lipid peroxidation induced endogenously was increased, however, suggesting a state of increased oxidative stress likely exists in vivo. Furthermore, changes in the rate of lipid peroxidation occurring during the propagation phase were also affected by diabetes. This implies possible changes in lipid composition or structure. Analysis indicated that the factors protecting mitochondria from lipid peroxidation differ from those involved in protecting the transcription system, and that both are independent of free radical scavenger levels. These results suggested that diabetes alters mitochondrial exposure and/or response to reactive species and provided clues to the role of oxidant stress in the development of diabetes-associated mitochondrial dysfunction.

Amidines↗

PubMed2000

Mitochondrial disease: beyond etiology unknown.

Mitochondrial dysfunction is now recognized as a relatively common cause of degenerative disease in children. Mutations in either the mitochondrial or the nuclear genome that cause errors in the synthesis of enzymes essential for energy production and metabolism lead to a wide variety of pediatric problems, including developmental delays, sensorimotor impairment, seizures, diabetes, and organ failure. This article reviews the role of mitochondria in health and illness, discusses the clinical aspects of mitochondrial dysfunction, describes the experiences of three children with mitochondrial disease, and presents nursing strategies for affected families.

Adult↗

PubMed2002

Retinal voltage-dependent anion channel: characterization and cellular localization.

PURPOSE: To characterize and localize retinal voltage-dependent anion channel (VDAC) and to understand its possible contribution to mitochondrial function and dysfunction. METHODS: VDAC was characterized by a method involving purification from isolated mitochondria and reconstitution into a planar lipid bilayer (PLB). The permeability transition pore (PTP) was monitored by Ca(2+) accumulation in isolated mitochondria and swelling of mitochondria. Localization was studied by immunocytochemistry and in situ hybridization. RESULTS: Retinal VDACs exhibited the electrophysiological fingerprint of the VDAC superfamily. It had a maximal chord conductance of 3.7 +/- 0.1 nanosiemens (nS) in 1 M NaCl, and a voltage-dependent conductance that was highest at transmembrane potential close to zero. It was modulated by glutamate, which decreased the channel's open probability, and by La(3+) and ruthenium amine binuclear complex (Ru360), which closed the channel. Energized and freshly prepared retinal mitochondria accumulated Ca(2+) that is inhibited by La(3+) ruthenium red and Ru360. Subsequent to Ca(2+) accumulation, mitochondria released the accumulated Ca(2+), probably through activation of the PTP. Ru360 inhibited Ca(2+) release and mitochondrial swelling. VDAC was present in mitochondria of all retinal cell types: photoreceptor, bipolar, horizontal, amacrine, and ganglion cells. Most cells primarily expressed VDAC-1, but they also expressed VDAC-2 and -3. CONCLUSIONS: These results suggest that VDAC is involved in PTP activity and/or regulation and thus is an important player in retinal degeneration associated with PTP-mediated mitochondrial dysfunction.

Animals↗

PubMedDate not supplied

Betulinic acid: a new chemotherapeutic agent in the treatment of neuroectodermal tumors.

We identified betulinic acid (BetA) as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing's sarcoma cells representing the most common solid tumors of childhood. BetA induced apoptosis independent of wild-type p53 protein and accumulation of death-inducing ligand/receptor systems such as CD95. BetA had a direct effect on mitochondria resulting in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-XL that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria conferred resistance to BetA at the level of mitochondrial dysfunction, protease activation and nuclear fragmentation. Neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis remained sensitive to treatment with BetA suggesting that BetA may bypass some forms of resistance. Moreover, BetA exhibited potent antitumor activity on primary tumor cell cultures from all neuroblastoma (4/4), all medulloblastoma (4/4) and most glioblastoma patients (20/24) ex vivo. These findings suggest that BetA may be a promising new agent in the treatment of neuroectodermal tumors in vivo.

Antineoplastic Agents, Phytogenic↗

PubMed1998

S-[(1 and 2)-phenyl-2-hydroxyethyl]cysteine-induced alterations in renal mitochondrial function in male Fischer-344 rats.

Previous studies from our laboratory have shown that mitochondrial dysfunction may be an important early event in S-[(1 and 2)-phenyl-2-hydroxyethyl]cysteine (PHEC)-induced cytotoxicity in isolated rat renal proximal tubules. The present study has therefore examined in more detail PHEC-induced mitochondrial dysfunction, both in vivo and in vitro, using isolated renal cortical mitochondria. Renal cortical mitochondria isolated from PHEC-treated rats in vivo showed depressed effects on the mitochondrial respiration and oxidative phosphorylation in both a dose (0, 250, and 500 micromol/kg iv)- and time (0-24 h)-dependent manner in the presence of both succinate (Site 2) and malate plus alpha-ketoglutarate (Site 1) as respiratory substrates, with initial significant depression occurring as early as 4 h following treatment with 500 micromol PHEC/kg. Similar mitochondrial dysfunctions were observed in vitro in concentration- and time-dependent manners with both respiratory substrates. PHEC also caused a marked dose-dependent inhibition of mitochondrial succinate dehydrogenase and NADH cytochrome c reductase activities both in vivo and in vitro, with initial inhibition occurring as early as 4 h after in vivo administration and 45 min after exposure to PHEC in vitro, while the NADH dehydrogenase activity was not considerably inhibited. The mitochondrial ATPase activity was significantly decreased 4 and 24 h following treatment with PHEC (500 micromol/kg). These results suggest that PHEC exerts its inhibitory effect on the mitochondrial respiration and oxidative phosphorylation through the action on the mitochondrial electron transport chain. PHEC significantly reduced the activity of adenine nucleotide translocase as well as the net uptake of substrates by mitochondria without affecting their efflux within 2-4 h after its injection (500 micromol/kg). On the other hand, significant renal damage, as assessed by morphological study, appeared as early as 24 h following such treatment. The observation of similar effects after both in vivo and in vitro exposures may suggest that the effect on mitochondria may have a pathogenic role in PHEC-induced renal injury in rats. PHEC produces mitochondrial toxicity that results from an inactivation of mitochondrial anionic substrate transporters as well as from an inhibition of activities of adenine nucleotide translocase and dehydrogenases.

Animals↗

PubMed2002

Mitochondrial involvement in amyotrophic lateral sclerosis.

The causes of motor neuron death in amyotrophic lateral sclerosis (ALS) are so far unknown. The involvement of mitochondria in the disease was initially suggested by ultrastructural studies. More recently these observations have been supported by studies of mitochondrial function in ALS. Alterations in the activity of complexes which make up the mitochondrial electron transport chain have been recorded as well as mutations in the mitochondrial genome. The calcium buffering function of the mitochondria may also be affected in the disease. This review will discuss how mitochondrial dysfunction could be of relevance in ALS and the evidence that an alteration of mitochondrial function is a feature of the disease. The way in which the involvement of mitochondria fits with other aetiological hypotheses for ALS will also be discussed.

Amyotrophic Lateral Sclerosis↗

PubMedDate not supplied

Hydrogen peroxide generation by mitochondria isolated from regionally ischemic and nonischemic dog myocardium.

We occluded the left anterior descending coronary artery of anesthetized, open-chest dogs, for 1 or 2 h. Some hearts were reperfused for 1 h after 1 h of ischemia. We isolated mitochondria from the central ischemic zone (CIZ) and a surrounding nonischemic zone (NIZ) of the left ventricle, and assayed H2O2 production using a horseradish peroxidase-dual wavelength spectrophotometric technique. Mitochondria, studied in the absence of exogenous respiratory chain inhibitors, generated H2O2 during State 4 respiration with succinate as the substrate. NIZ mitochondria in all groups produced ca. 1.5 nmols H2O2/min/mg protein (no significant differences between groups). The State 4 O2 consumption rates of NIZ mitochondria from hearts subjected to 1 h ischemia plus reperfusion, or 2 h of ischemia (ca. 30 nmols/min/mg) were significantly higher than that of NIZ mitochondria of hearts subjected to only 1 h of ischemia (23 nmols/min/mg). Thus, the ratio between H2O2 produced and State 4 O2 consumption fell from 6.5% to 5%. Mitochondria from all CIZ samples had State 4 O2 consumption rates that were not different from corresponding NIZ values. However CIZ mitochondria of hearts subjected to 1 h ischemia without reperfusion produced less H2O2 (1.1 +/- 0.1 nmols/min/mg), and had a slightly reduced H2O2/O2 ratio (4.4 +/- 0.7%), compared with their NIZ samples (1.5 +/- 0.1 nmols/min/mg; 5.3%). Reperfusion after 1 h of ischemia abolished these regional differences. The CIZ mitochondria from hearts subjected to 2 h ischemia produced only 0.75 +/- 0.22 nmols H2O2/min/mg (2.5% of State 4 O2 consumption). These values were 50% of corresponding NIZ values, and were significantly less than for any other group or tissue region. If similar phenomena occur in conscious animals subjected to incomplete regional ischemia, especially of relatively brief duration or if accompanied by reduced intracellular defenses against oxidants such as H2O2, they suggest that mitochondria persist as H2O2 sources and so may contribute to the oxidant load and myocardial dysfunction.

Adenosine Diphosphate↗

PubMed2005

Release of cytochrome c from isolated mitochondria by etoposide.

The efficacy of chemotherapeutic agents on tumor cells has been shown to be modulated by tumor suppressor gene p53 and its target genes such as Bcl-2 family members (Bax, Noxa, and PUMA). However, various chemotherapeutic agents can induce cell death in tumor cells that do not express the functional p53, suggesting that some chemotherapeutic agents may induce cell death in a p53-independent pathway. Here we showed that etoposide can induce the similar degree of cell death in p53-deficient HCT 116 cells, whereas 5'-FU-mediated cell death is strongly dependent on the existence of functional p53 in HCT 116 cells. Further, we provide the evidence that etoposide can induce the cytochrome c release from isolated mitochondria, and etoposide-induced cytochrome c release is not accompanied with the large amplitude swelling of mitochondria. These data suggest that etoposide can directly induce the mitochondrial dysfunction irrespective of p53 status, and it may, at least in part, account for the p53-independent pathway in cell death induced by chemotherapeutic agents.

Animals↗

PubMed1997

Fialuridine is phosphorylated and inhibits DNA synthesis in isolated rat hepatic mitochondria.

Fialuridine (FIAU) is a thymidine analog effective against hepatitis B virus. Toxicity associated with FIAU treatment included clinical signs consistent with mitochondrial dysfunction, including severe lactic acidosis. To understand further the mechanism of FIAU toxicity, we examined the effect of FIAU on DNA synthesis in mitochondria. Mitochondria isolated from livers of naive rats were treated in vitro with concentrations of FIAU or FIAU triphosphate (FIAU-TP) ranging from 0.1 to 200 microM. A 14 or 32% decrease in mitochondrial DNA synthesis compared to controls was observed when isolated mitochondria were treated with 25 microM FIAU or FIAU-TP, respectively. Since it is thought that nucleosides must be phosphorylated to inhibit DNA polymerase, studies were conducted to determine whether isolated rat mitochondria could phosphorylate FIAU. Results using lanthanum chloride precipitation and HPLC analysis showed that enzymes present in a mitochondrial lysate were capable of phosphorylating FIAU to form FIAU monophosphate.

Animals↗

PubMed2003

Bcl-2 on the endoplasmic reticulum: protecting the mitochondria from a distance.

Bcl-2 has been described both as an inhibitor of programmed cell death and as an inhibitor of mitochondrial dysfunction during apoptosis. It is still not clear what biochemical activity of Bcl-2 is responsible for its function, but increasing evidence indicates that a functional activity of Bcl-2 on the endoplasmic reticulum (ER) protects mitochondria under diverse circumstances. Indeed, an emerging hypothesis is that, during apoptosis, the Bcl-2 family regulates ER-to-mitochondrion communication by BH3-only proteins and calcium ions and thereby triggers mitochondrial dysfunction and cell death.

Animals↗

PubMed2005

Nitric oxide induces osteoblast apoptosis through a mitochondria-dependent pathway.

Osteoblasts contribute to bone remodeling. Nitric oxide can regulate osteoblast activities. In this study, we attempted to evaluate the pathophysiological effects of nitric oxide on osteoblasts and its possible mechanism using neonatal rat calvarial osteoblasts as the experimental model. Exposure of osteoblasts to sodium nitroprusside, a nitric oxide donor, decreased alkaline phosphatase activities and cell viability in a concentration- and time-dependent manner. Apoptotic analysis revealed that sodium nitroprusside time-dependently increased the percentages of osteoblasts undergoing apoptosis. Administration of sodium nitroprusside reduced the mitochondrial membrane potential of osteoblasts. In parallel with the mitochondrial dysfunction, levels of intracellular reactive oxygen species and cytochrome c were significantly elevated following sodium nitroprusside administration. Exposure of osteoblasts to sodium nitroprusside significantly increased caspase-3 activity. Results of this study show that nitric oxide, decomposed from sodium nitroprusside, can induce osteoblast apoptosis through a mitochondrion-dependent cascade that causes mitochondrial dysfunction, release of intracellular reactive oxygen species and cytochrome c from mitochondria to cytoplasm, and activation of caspase-3.

Alkaline Phosphatase↗

PubMed2007

Mitochondrial function in liver disease.

Oxidative stress is involved in the pathogenesis and progression of different liver diseases, such as alcoholic liver disease and biliary cirrhosis. The increased mitochondrial production of O2(-) at complexes I and III, and consequently of H2O2 and other reactive oxygen species (ROS), triggered by NADH overproduction seems the major cause of mitochondrial and cellular oxidative stress and damage in chronic alcoholism. The mitochondrial oxidative stress renders hepatocytes susceptible to ethanol- or acetaldehyde-induced mitochondrial membrane permeability transition (MMPT) and apoptosis. Nitrosative stress contributes to cell death by peroxynitrite formation. The expression of the death receptor ligand CD95 is also up-regulated by acetaldehyde metabolism. Consequently, a dual mechanism, NADH-driven MMPT and CD95-mediated apoptosis, involving in both cases acetaldehyde metabolism and ROS production, operates in ethanol-induced apoptosis. In the biliary cirrhosis induced by chronic cholestasis, liver mitochondria show increased H2O2 production and GSH depletion and oxidation. Dysfunctional hepatocytes, with a loss in mitochondrial cardiolipin and decreased mitochondrial membrane potential evolve during cholestasis to apoptosis. Ursodeoxycholic acid prevents enlargement of this population as well as mitochondrial oxidative stress. Mitochondrial oxidative stress precedes the initiation and execution of hepatocyte apoptosis in chronic alcoholism and biliary cirrhosis. We suggest that overproduction of mitochondrial NADH is the primary cause for the development of alcoholic and non-alcoholic liver disease by a situation of chronic mitochondrial oxidative stress, which should be considered the second hit that renders hepatocytes susceptible to cell injury and apoptosis.

Animals↗

PubMed1998

Poor recovery of mitochondrial redox state in CA1 after transient forebrain ischemia in gerbils.

BACKGROUND AND PURPOSE: Several investigations have detected evidence of apoptosis in delayed neuronal death, but controversy prevails regarding this point. Recent studies have implicated mitochondria in apoptotic events. To explore relationships between delayed neuronal death and dysfunction of the respiratory chain, we analyzed mitochondrial redox changes in the gerbil hippocampus. METHODS: We assessed the mitochondrial redox state in gerbil hippocampus before, during, and at various time points after 5 minutes of forebrain ischemia. The redox state was examined with a low-temperature fluorometer. Fluorescence signals of flavoprotein and NADH were measured, and their fluorescence ratio was calculated as a mitochondrial redox ratio (MRR) equal to flavoprotein/(flavoprotein+NADH). RESULTS: Ischemia increased NADH and decreased flavoprotein signals in all hippocampal areas, but reduction in MRR was greater in CA1 than in other areas of the hippocampus. Immediately after recirculation, MRR recovery was delayed in the CA1 and the dentate gyrus, and the reduction in MRR persisted in CA1. CONCLUSIONS: These results suggest that during ischemia CA1 experiences more pronounced hypoxia (state V) than less vulnerable regions. Persistent MRR reduction in CA1 is attributed to dysfunction of the electron transport system, and this phenomenon may be importantly involved in apoptosis.

Animals↗

PubMed2002

The sarcoplasmic reticulum in disease and smooth muscle dysfunction: therapeutic potential.

The functions of the sarcoplasmic reticulum (SR) in diseased smooth muscle can be investigated by measuring Ca2+ transients in response to agonist application, and through cell homogenization, isolation of microsomes and measurements of Ca-ATPase activity (SERCA). Such measurements have indicated that contractile dysfunction may be associated with degradation of SERCA in some systems, such as hypertrophied bladder smooth muscle. However, the postulated roles of the SR in smooth muscle function vary from one tissue to another and SR may mediate relaxation as well as contraction. Function seems to depend on the precise location of the SR with respect to the plasma membrane and its Ca2+-activated ion channels, the Ca2+ transporters, the cavaeoli, the mitochondria, and the contractile machinery. In diseases characterized by smooth muscle dysfunction, the size of the smooth muscle cells is frequently altered, as occurs in the hypertrophy seen in gut and bladder obstruction and hypertension. This will inevitably lead to alterations in the morphology and the function of the SR. Any therapeutic potential awaits considerable advances in our understanding of the systems in individual smooth muscles and the development of selective drugs.

Animals↗