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PubMed2003

Profiling genes related to mitochondrial function in mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Since mitochondrial dysfunction plays an important role in the pathogenesis of dopaminergic neurodegeneration in Parkinson's disease, we determined the expression of genes related to mitochondrial function in the substantia nigra of mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a cDNA array. MPTP treatment significantly depleted striatal dopamine, but did not result in apparent neuronal loss in the substantia nigra at 3 and 18 days post-treatment. We also examined changes in genes in the hypothalamus, a region containing dopaminergic neurons that are relatively resistant to MPTP. Finally, we confirmed those genes identified by microarrays as differentially expressed in the substantia nigra but not in the hypothalamus using in situ hybridization. Our results demonstrated that MPTP significantly changed the expressions of six genes in nigral neurons, four of which were related to the mitochondrial electron transport chain: the NADH-ubiquinone oxidoreductase 13 kDa B subunit, the NADH-ubiquinone oxidoreductase MNLL subunit, cytochrome c, and the cytochrome c oxidase Va subunit. Two other differentially expressed genes were the dihydropyridine-sensitive L-type calcium channel alpha-2 subunit precursor and type III alpha-1 procollagen. None of these six genes are encoded by mitochondrial DNA. The potential significance of these gene alterations in the context of Parkinson's disease is discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

A digitized-fluorescence-imaging study of mitochondrial Ca2+ increase by doxorubicin in cardiac myocytes.

The objective of the present study was to investigate the role of mitochondrial Ca2+ in doxorubicin-induced cell injury. The effect of doxorubicin on cultured cells was investigated by digitized fluorescence imaging. The Ca2+ sensitive fluorescent dye fura-2 was used to estimate cytosolic, mitochondrial and total cellular Ca2+. Rhodamine 123 was used to estimate the mitochondrial membrane potential, and cellular ATP was determined by h.p.l.c. The data showed that doxorubicin induced greater-than-2-fold increases in mitochondrial Ca2+ before changes in cytosolic Ca2+ could be detected. An increase in mitochondrial Ca2+ paralleled the observed dissipation in mitochondrial membrane potential. Cellular ATP levels appeared to decrease as a result of mitochondrial dysfunction, which in turn produced greater-than-2-fold increases in cytosolic Ca2+. The data suggest that doxorubicin-induced alterations in mitochondrial Ca2+ homoeostasis are associated with a dissipation in energy conservation, which may result in cell injury.

Adenosine Triphosphate↗
PubMed2003

Antisense inhibition of mitochondrial pyruvate dehydrogenase E1alpha subunit in anther tapetum causes male sterility.

We hypothesized that cytoplasmic male sterility (CMS) in sugar beet may be the consequence of mitochondrial dysfunctions affecting normal anther development. To test the hypothesis, we attempted to mimic the sugar beet CMS phenotype by inhibiting the expression of mitochondrial pyruvate dehydrogenase (PDH), which is essential for the operation of the tricarboxylic acid (TCA) cycle. Screening with a cDNA library of sugar beet flower buds allowed the identification of two PDH E1alpha subunit genes (bvPDH_E1alpha-1 and bvPDH_E1alpha-2). bvPDH_E1alpha-1 was found to be highly expressed in tap roots, whereas bvPDH_E1alpha-2 was expressed most abundantly in flower buds. Green fluorescent protein (GFP) fusion of bvPDH_E1alpha revealed mitochondrial targeting properties. A 300-bp bvPDH_E1alpha-1 cDNA sequence (from +620 to +926) was connected to a tapetum-specific promoter in the antisense orientation and then introduced into tobacco. Antisense expression of bvPDH_E1alpha-1 resulted in conspicuously decreased endogenous bvPDH_E1alpha-1 transcripts and male sterility. The tapetum in the male-sterile anthers showed swelling or abnormal vacuolation. It is also worth noting that in the sterile anthers, cell organelles, such as elaioplasts, tapetosomes and orbicules were poorly formed and microspores exhibited aberrant exine development. These features are shared by sugar beet CMS. The results thus clearly indicate that inhibition of PDH activity in anther tapetum is sufficient to cause male sterility, a phenocopy of the sugar beet CMS.

Amino Acid Sequence↗
PubMed1997

Identification of inheritance modes of mitochondrial diseases by introduction of pure nuclei from mtDNA-less HeLa cells to patient-derived fibroblasts.

A nuclear genome delivery system was developed to deduce the modes of inheritance of the clinical phenotypes observed in patients with mitochondrial diseases by transfer of pure nuclei from normal cells to fibroblasts from the patients. The problem of possible contamination of the nuclei with a small amount of mtDNA was overcome by using mtDNA-less (rho0) human cells as nuclear donors. In this study, intercellular transfer of pure nuclei was carried out by simple fusion of rho0 HeLa cells with 533 fibroblasts from a patient with a fatal mitochondrial disease, which were deficient in cytochrome c oxidase and succinate dehydrogenase activities. The results showed that the cytochrome c oxidase and succinate dehydrogenase activities were restored by the introduction of pure HeLa nuclei, suggesting that the observed phenotypes of mitochondrial dysfunction were not due to mtDNA mutations but to nuclear, recessive mutations. Thus, our nuclear transfer system is effective for determining whether a mitochondrial or nuclear genome of a patient is responsible for a disease and whether deficiency of mitochondrial enzymes, including enzymes exclusively encoded by nuclear genomes, is transmitted in a nuclear recessive or nuclear dominant way, providing the parents of the patients with valuable information for genetic counseling on the risk of mitochondrial diseases in their next babies.

Adenosine Triphosphatases↗
PubMed1999

ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria.

1. Mitochondrial dysfunction, secondary to excessive accumulation of Ca2+, has been implicated in cardiac injury. We here examined the action of potassium channel openers on mitochondrial Ca2+ homeostasis, as these cardioprotective ion channel modulators have recently been shown to target a mitochondrial ATP-sensitive K+ channel. 2. In isolated cardiac mitochondria, diazoxide and pinacidil decreased the rate and magnitude of Ca2+ uptake into the mitochondrial matrix with an IC50 of 65 and 128 microM, respectively. At all stages of Ca2+ uptake, the potassium channel openers depolarized the mitochondrial membrane thereby reducing Ca2+ influx through the potential-dependent mitochondrial uniporter. 3. Diazoxide and pinacidil, in a concentration-dependent manner, also activated release of Ca2+ from mitochondria. This was prevented by cyclosporin A, an inhibitor of Ca2+ release through the mitochondrial permeability transition pore. 4. Replacement of extramitochondrial K+ with mannitol abolished the effects of diazoxide and pinacidil on mitochondrial Ca2+, while the K+ ionophore valinomycin mimicked the effects of the potassium channel openers. 5. ATP and ADP, which block K+ flux through mitochondrial ATP-sensitive K+ channels, inhibited the effects of potassium channel openers, without preventing the action of valinomycin. 6. In intact cardiomyocytes, diazoxide also induced mitochondrial depolarization and decreased mitochondrial Ca2+ content. These effects were inhibited by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid. 7. Thus, potassium channel openers prevent mitochondrial Ca2+ overload by reducing the driving force for Ca2+ uptake and by activating cyclosporin-sensitive Ca2+ release. In this regard, modulators of an ATP-sensitive mitochondrial K+ conductance may contribute to the maintenance of mitochondrial Ca2+ homeostasis.

Adenosine Diphosphate↗
PubMed1999

Cell cycle delay, mitochondrial stress and uptake of hydrophobic cations induced by sunscreens in cultured human cells.

Reports of systemic absorption of sunscreens prompted a study of the effects of emulsions of 3 commonly used sunscreens on cultured human cells; vegetable oil and paraffin oil were used as controls. Ethylhexyl p-methoxycinnamate (EHMC), octyl p-dimethylaminobenzoate (PABA) and oxybenzone (OB) inhibited cell growth and DNA synthesis and retarded cycle progression from G1 in the dose range 25-100 micrograms/mL. An extended period of exposure (up to 24 h) was required for maximum uptake of sunscreens and for inhibition of cell growth. Melano-cytes and fibroblasts tended to be more resistant than tumor cell lines (melanoma, cervical carcinoma). Sunscreens had no major effects on the transcription of certain genes, as judged by the activity of reporter constructs driven by the p53, c-fos and metal response (sheep metallothionein Ia promoter) elements and transfected into a human melanoma cell line (MM96L). The activity of the cytomegalovirus promoter was also not affected. A cell line (CI80-13S) with mitochondrial dysfunction was significantly more sensitive to growth inhibition by EHMC and PABA than the other cell lines tested. Treatment of MM96L with the mitochondrial inhibitor ethidium bromide sensitized the cells to killing by cotreatment with sunscreens, in association with increased cellular uptake of ethidium bromide. These results established conditions for studying the action of sunscreens on cultured human cells. Further studies are required to determine whether the mitochondrial stress and changes in drug uptake associated with sunscreens in the above cell lines are relevant to their action in vivo.

Cations↗
PubMed2003

Only transient increase of serum CoQ subset 10 during long-term CoQ10 therapy in mitochondrial ophthalmoplegia.

BACKGROUND: Coenzyme Q10 (CoQ10) is frequently administered in mitochondrial diseases. Mitochondrial dysfunction and CoQ10 treatment was also proposed in neurodegenerative disorders as amyotrophic lateral sclerosis and Parkinsons disease. PATIENTS AND METHODS: Seventeen patients with mitochondrial CPEO were treated with CoQ10 (dosage: 0.60 1.80 mg/kg body wt) in an open trial. Serum levels of CoQ10 were monitored before and after 6-9 and 12-15 months of CoQ10 therapy. CoQ10 concentration in muscle was measured in all patients before treatment. RESULTS: Prior to treatment CoQ10 concentration in muscle was normal in all patients. Eight patients completed the study after 12-15 months. Prior to treatment there was no correlation between CoQ10 in muscle and serum. There was no inverse correlation of serum lactate with CoQ10 in muscle before and in serum before and during therapy. CoQ10 serum level and body weight related CoQ10 dosage correlated significantly after 6-9 months but not after 12-15 months (p = 0.043 and n. s., respectively). During continued administration of CoQ10 the CoQ10 serum level was increased 2.76 +/- 1.00-fold after 6-9 months (range: 1.04-3.80). but returned to 1.70 +/- 0.98-fold after 12-15 months (range: 0.91-3.83). Serum lactate did not significantly change during treatment. There was no effect of CoQ10 treatment on signs and symptoms. CONCLUSION: The only transient increase of CoQ10 in serum has to be considered in any low dose long-term treatment with CoQ10.

Adolescent↗
PubMed2003

Transcription factors c-Jun/activator protein-1 and nuclear factor-kappa B in oxidative stress response in mitochondrial diseases.

Mitochondrial dysfunction leads to oxygen free radical (ROS) generation with consequent oxidative stress and cellular damage. Recently, activation of the cellular antioxidant system and apoptosis were demonstrated in skeletal muscle fibres from patients with mitochondrial diseases, but the underlying mechanisms remain unknown. Hydrogen peroxide, a by-product of ROS generation, is a chemical inducer of gene expression able to activate apoptosis and to promote the antioxidant response through the activation of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) transcription factor. Using immunohistochemistry and confocal microscopy, we evaluated the expression of NF-kappaB and AP-1 in muscle biopsies from patients with mitochondrial disease. In addition, we examined the expression of factors involved in their activation, such as NF-kappaB inducing kinase (NIK) and phosphorylated Jun-N-terminal kinase (p-JNK). Most fibres with respiratory chain dysfunction displayed nuclear staining for activated c-Jun/AP-1, but not for NF-kappaB. The same fibres reacted for p-JNK. Only some ragged red fibres immunoreacted for NIK. These data suggest that AP-1 is involved in the oxidative stress response in muscle fibres from patients with mitochondrial disease.

Humans↗
PubMed2003

The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNALys gene.

In a case of childhood-onset myoclonus epilepsy with "ragged-red fibers" (MERRF), a hitherto unreported mutation within the mitochondrial tRNA(Lys) gene was identified as the cause of the disease. Substitution G8361A was maternally inherited, heteroplasmic in all tissues tested, and correlated with mitochondrial dysfunction in individual muscle fibers. The growing number of MERRF-associated mutations within the tRNA(Lys) gene affirms the specific role of this mitochondrial tRNA in the pathogenesis of the disease.

Amino Acid Substitution↗
PubMed1992

Structural and functional mitochondrial abnormalities associated with high levels of partially deleted mitochondrial DNAs in somatic cell hybrids.

Kearns-Sayre syndrome (KSS) is a progressive and ultimately fatal human encephalomyopathy that is associated with large-scale deletions of mitochondrial DNA (mtDNA). To gain new insights into the developmental pathobiology of this disease, we studied the maintenance and expression of deleted mtDNAs (delta-mtDNAs) in somatic cell hybrids generated by fusion of HeLacot cells with a KSS fibroblast clone containing both wild-type and delta-mtDNAs. We observed that delta-mtDNAs were preferentially maintained over the KSS wild-type mtDNAs (wt-mtDNAs) in almost all isolated hybrid clones. Mitochondrial metabolism was not compromised in hybrids containing as much as 70-79% delta-mtDNAs. Two clones containing more than 99% delta-mtDNA were severely deficient in oxidative phosphorylation and exhibited abnormal, enlarged mitochondria. These clones had undetectable levels of mtDNA-encoded polypeptides, but contained normal amounts of a nuclear DNA-encoded mitochondrial protein. The data suggest a nonrandom pattern of mtDNA segregation in the triplasmic hybrids and a correlation among delta-mtDNA, structural mitochondrial abnormalities, and mitochondrial dysfunction.

Cell Division↗
PubMed1993

Wolfram syndrome: a mitochondrial-mediated disorder?

Mitochondrial DNA mutations cause several human diseases, (eg, Leber's hereditary optic neuropathy). Wolfram syndrome (characterised by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) also has, in some cases, a mitochondrial origin. The disease, often familial, has been well documented as an autosomal recessive disorder, and most of the clinical phenotypes are consistent with an ATP supply defect that is often seen in mitochondrial-mediated disorders. We propose a dual genome defect model for Wolfram syndrome in which nuclear genetic defects or mitochondrial genetic defects can independently lead to the disease. This model suggests that besides a mitochondrial gene defect alone, a nuclear gene defect, which interferes with the normal function of mitochondria (probably with a normal mitochondrial genome), can also be the underlying explanation for the pleiotropic features of Wolfram syndrome. This hypothesis explains how an autosomal recessive disorder can result in mitochondrial dysfunction, and has a general application in the identification of candidate genes for the various important phenotypes (eg, deafness and diabetes mellitus) seen in mitochondrial disorders.

DNA, Mitochondrial↗
PubMed1999

Mitochondria in organismal aging and degeneration.

Several lines of experimentation support the view that the genetic, biochemical and bioenergetic functions of somatic mitochondria deteriorate during normal aging. Deletion mutations of the mitochondrial genome accumulate exponentially with age in nerve and muscle tissue of humans and multiple other species. In muscle, a tissue that undergoes age-related fiber loss and atrophy in humans, there is an exponential rise in the number of cytochrome-oxidase-deficient fibers, which is first detectable in the fourth decile of age. Most biochemical studies of animal mitochondrial activity indicate a decline in electron transport activity with age, as well as decreased bioenergetic capacity with age, as measured by mitochondrial membrane potential. Mitochondrial mutations may be both the result of mitochondrial oxidative stress, and cells bearing pure populations of pathogenic mitochondrial mutations are sensitized to oxidant stress. Oxidant stress to mitochondria is known to induce the mitochondrial permeability transition, which has recently been implicated in the release of cytochrome c and the initiation of apoptosis. Thus several lines of evidence support a contribution of mitochondrial dysfunction to the phenotypic changes associated with aging.

Aging↗
PubMed2000

Apoptosis in neurodegenerative disorders.

Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death--apoptosis--involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.

Animals↗
PubMed2006

Mitochondria and cancer: is there a morphological connection?

Mitochondria are key players in several cellular functions including growth, division, energy metabolism, and apoptosis. The mitochondrial network undergoes constant remodelling and these morphological changes are of direct relevance for the role of this organelle in cell physiology. Mitochondrial dysfunction contributes to a number of human disorders and may aid cancer progression. Here, we summarize the recent contributions made in the field of mitochondrial dynamics and discuss their impact on our understanding of cell function and tumorigenesis.

Animals↗
PubMed2007

Mitochondrial superoxide radicals mediate programmed cell death in Trypanosoma cruzi: cytoprotective action of mitochondrial iron superoxide dismutase overexpression.

Trypanosoma cruzi undergo PCD (programmed cell death) under appropriate stimuli, the mechanisms of which remain to be established. In the present study, we show that stimulation of PCD in T. cruzi epimastigotes by FHS (fresh human serum) results in rapid (<1 h) externalization of phosphatidylserine and depletion of the low molecular mass thiols dihydrotrypanothione and glutathione. Concomitantly, enhanced generation of oxidants was established by EPR and immuno-spin trapping of radicals using DMPO (5,5-dimethylpyrroline-N-oxide) and augmentation of the glucose flux through the pentose phosphate pathway. In the early period (<20 min), changes in mitochondrial membrane potential and inhibition of respiration, probably due to the impairment of ADP/ATP exchange with the cytosol, were observed, conditions that favour the generation of O2*-. Accelerated rates of mitochondrial O2*- production were detected by the inactivation of the redox-sensitive mitochondrial aconitase and by oxidation of a mitochondrial-targeted probe (MitoSOX). Importantly, parasites overexpressing mitochondrial FeSOD (iron superoxide dismutase) were more resistant to the PCD stimulus, unambiguously indicating the participation of mitochondrial O2*- in the signalling process. In summary, FHS-induced PCD in T. cruzi involves mitochondrial dysfunction that causes enhanced O(2)(*-) formation, which leads to cellular oxidative stress conditions that trigger the initiation of PCD cascades; moreover, overexpression of mitochondrial FeSOD, which is also observed during metacyclogenesis, resulted in cytoprotective effects.

Animals↗
PubMed2006

Crucial mitochondrial impairment upon CDC48 mutation in apoptotic yeast.

Mutation in CDC48 (cdc48(S565G)), a gene essential in the endo-plasmic reticulum (ER)-associated protein degradation (ERAD) pathway, led to the discovery of apoptosis as a mechanism of cell death in the unicellular organism Saccharomyces cerevisiae. Elucidating Cdc48p-mediated apoptosis in yeast is of particular interest, because Cdc48p is the highly conserved yeast orthologue of human valosin-containing protein (VCP), a pathological effector for polyglutamine disorders and myopathies. Here we show distinct proteomic alterations in mitochondria in the cdc48(S565G) yeast strain. These observed molecular alterations can be related to functional impairment of these organelles as suggested by respiratory deficiency of cdc48(S565G) cells. Mitochondrial dysfunction in the cdc48(S565G) strain is accompanied by structural damage of mitochondria indicated by the accumulation of cytochrome c in the cytosol and mitochondrial enlargement. We demonstrate accumulation of reactive oxygen species produced predominantly by the cytochrome bc1 complex of the mitochondrial respiratory chain as suggested by the use of inhibitors of this complex. Concomitantly, emergence of caspase-like enzymatic activity occurs suggesting a role for caspases in the cell death process. These data strongly point for the first time to a mitochondrial involvement in Cdc48p/VCP-dependent apoptosis.

Adenosine Triphosphatases↗
PubMed1999

Death signals from the B cell antigen receptor target mitochondria, activating necrotic and apoptotic death cascades in a murine B cell line, WEHI-231.

B cell antigen receptor (BCR)-mediated cell death has been proposed as a mechanism for purging the immune repertoire of anti-self specificities during B cell differentiation in bone marrow. Mitochondrial alterations and activation of caspases are required for certain aspects of apoptotic cell death, but how the mitochondria and caspases contribute to BCR-mediated cell death is not well understood. In the present study, we used the mouse WEHI-231 B cell line to demonstrate that mitochondrial alterations and activation of caspases are indeed participants in BCR-mediated cell death. The peptide inhibitor of caspases, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), blocked cleavage of poly(ADP-ribose) polymerase and various manifestation of nuclear apoptosis such as nuclear fragmentation, hypodiploidy and DNA fragmentation, indicating that signals from the BCR induced the activation of caspases. In addition, z-VAD-fmk delayed apoptosis-associated changes in cellular reduction-oxidation potentials as determined by hypergeneration of superoxide anion, as well as exposure of phosphatidylserine residues in the outer plasma membrane. By contrast, although z-VAD-fmk retarded cytolysis, it was incapable of preventing disruption of the plasma membrane even under the same condition in which it completely blocked nuclear apoptosis. Mitochondrial membrane potential loss was also not blocked by z-VAD-fmk. Bongkrekic acid, a specific inhibitor of mitochondrial permeability transition pores, suppressed not only the mitochondrial membrane potential but also the change of plasma membrane permeability. Overexpression of Bcl-xL prevented mitochondrial dysfunction, nuclear apoptosis and membrane permeability cell death triggered by BCR signal transduction. These observations indicate that death signals from BCR may first cause mitochondrial alterations followed by activation of both necrotic and apoptotic cascades.

Amino Acid Chloromethyl Ketones↗
PubMed2005

Extracellular N-acetylaspartate depletion in traumatic brain injury.

N-Acetylaspartate (NAA) is almost exclusively localized in neurons in the adult brain and is present in high concentration in the CNS. It can be measured by proton magnetic resonance spectroscopy and is seen as a marker of neuronal damage and death. NMR spectroscopy and animal models have shown NAA depletion to occur in various types of chronic and acute brain injury. We investigated 19 patients with traumatic brain injury (TBI). Microdialysis was utilized to recover NAA, lactate, pyruvate, glycerol and glutamate, at 12-h intervals. These markers were correlated with survival and a 6-month Glasgow Outcome Score. Eleven patients died and eight survived. A linear mixed model analysis showed a significant effect of outcome and of the interaction between time of injury and outcome on NAA levels (p = 0.009 and p = 0.004, respectively). Overall, extracellular NAA was 34% lower in non-survivors. A significant non-recoverable fall was observed in this group from day 4 onwards, with a concomitant rise in lactate-pyruvate ratio and glycerol. These results suggest that mitochondrial dysfunction is a significant contributor to poor outcome following TBI and propose extracellular NAA as a potential marker for monitoring interventions aimed at preserving mitochondrial function.

Adult↗