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PubMed2006

Mitochondrial dysfunction induced by disease relevant AbetaPP and tau protein mutations.

Alzheimer's disease is characterized by two major pathological hallmarks: extracellular plaques consisting of amyloid beta peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Mutations in the amyloid beta-protein precursor (AbetaPP) have been linked to familial Alzheimer's disease. They are leading to increased amyloid beta production. Mutations in the tau gene have not been described in AD, but are leading to formation of neurofibrillary tangles very similar to filaments in AD brains, and are therefore of increasing relevance in AD research. Interestingly, our data indicate that mutations in AbetaPP gene and mutations in tau gene induce mitochondrial dysfunction and oxidative stress in cell culture models and transgenic mice. Thus, both Alzheimer relevant protein alterations seem to have synergistic actions probably at the level of mitochondria leading to synaptic dysfunction and apoptotic cell death.

Amyloid beta-Protein Precursor↗
PubMedDate not supplied

Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death.

Oxidative stress is increased in the retina in diabetes; the levels of oxidatively modified DNA and nitrosylated proteins are elevated, and antioxidant defense enzymes are impaired. The levels of superoxides are elevated in the retina, and the mitochondria become dysfunctional with proapoptotic protein, Bax, translocating from the cytosol into the mitochondria, and cytochrome c leaking out from the mitochondria. This is accompanied by increased retinal capillary cell apoptosis, and the formation of acellular capillaries and pericyte ghosts, the early signs of retinopathy in animal models of diabetic retinopathy. Inhibition of superoxides inhibits glucose -induced mitochondrial dysfunction, activation of caspase-3, and cell death in retinal capillary cells. In animal models, long-term administration of lipoic acid or other antioxidants inhibits the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine and capillary cell apoptosis in the retina. Understanding the role of mitochondria in the development of retinopathy in diabetes should help identify therapies that can neutralize superoxides and inhibit their dysfunction and, ultimately, the development of retinopathy.

Animals↗
PubMed1999

The PIM-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway.

We have examined potential mechanisms by which the Pim-1 kinase acts as a hematopoietic cell survival factor. Enforced expression of the wild type 33 kd (FD/hpim33) and 44 kd (FD/mpim44) Pim-1 proteins in murine factor-dependent FDCP1 cells prolonged survival after withdrawal of IL-3, while expression of a dominant negative Pim-1 protein (FD/pimNT81) shortened survival. Following removal of IL-3 FDCP1 cells exhibited loss of mitochondrial transmembrane potential and production of reactive oxygen species, as determined by flow cytometry analysis. The wild type Pim-1 proteins decreased these changes while the dominant negative protein enhanced mitochondrial dysfunction. The antiapoptotic activity of the kinases could not be attributed to modulation of glutathione, catalase, or superoxide dismutase activities. Both the FD/hpim33 and FD/mpim44 cells maintained expression of bcl-2 mRNA following cytokine removal, while a substantial decrease was seen in FD/neo cells. To modulate Bcl-2 protein levels, a bcl-2 antisense RNA construct was coexpressed with the wild type pim-1 cDNAs. FD/hpim33 cells with low cellular Bcl-2 protein levels had shortened cytokine-independent survival compared with FD/hpim33 clones with high Bcl-2 expression. However survival of FD/mpim44 cells after IL-3 withdrawal was substantially independent of cellular Bcl-2 protein levels. The 33 kd protein delayed, and the 44 kd protein completely prevented enhanced cell death associated with enforced expression of human Bax protein however. Our results suggest that the 33 kd Pim-1 kinase may enhance cell survival through cooperation with and regulation of bcl-2. In addition the 44 kd kinase may regulate the expression or activity of other pro- and anti-apoptotic members of the bcl-2 family.

Animals↗
PubMed2006

Expanding insights of mitochondrial dysfunction in Parkinson's disease.

The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.

Animals↗
PubMed2005

Okadaic acid induces JNK activation, bim overexpression and mitochondrial dysfunction in cultured rat cortical neurons.

Apoptosis via tau phosphorylation has been implicated in the selective neuronal losses seen in Alzheimer's disease (AD). Previous studies in vivo and in cultured neurons have shown that okadaic acid (OA) evokes tau phosphorylation to initiate a neurodegeneration that resembles the pathogenesis of AD. In an effort to identify additional key molecules in this neurodegeneration, we treated cultured rat neurons with OA and examined the apoptosis-related effects, such as changes in mitochondrial activity and expression levels of JNK, Bim, Bad, Bax and caspase-3. Western blotting revealed that phosphorylation of JNK and c-jun occurred first, followed by increased expression of Bim and subsequent caspase-3 activation in OA-treated neurons. In contrast, Bad levels decreased as early as 4 h after OA treatment. Immunocytochemistry showed that the increased phospho-JNK immunoreactivity was localized in the cytosol of degenerating neurons, while increased phospho-c-jun was localized in the nucleus. The mitochondria showed decreased membrane potential and increased swelling after OA treatment. Collectively, these data suggest that JNK- and Bim-related mitochondrial dysfunction is involved in OA-induced neurodegeneration.

Animals↗
PubMed2003

A review of the role of reactive oxygen and nitrogen species in alcohol-induced mitochondrial dysfunction.

Our understanding of the mechanisms involved in the development of alcohol-induced liver disease has increased substantially in recent years. Specifically, reactive oxygen and nitrogen species have been identified as key components in initiating and possibly sustaining the pathogenic pathways responsible for the progression from alcohol-induced fatty liver to alcoholic hepatitis and cirrhosis. Ethanol has been demonstrated to increase the production of reactive oxygen and nitrogen species and decrease several antioxidant mechanisms in liver. However, the relative contribution of the proposed sites of ethanol-induced reactive species production within the liver is still not clear. It has been proposed that chronic ethanol-elicited alterations in mitochondria structure and function might result in increased production of reactive species at the level of the mitochondrion in liver from ethanol consumers. This in turn might result in oxidative modification and inactivation of mitochondrial macromolecules, thereby contributing further to mitochondrial dysfunction and a loss in hepatic energy conservation. Moreover, ethanol-related increases in reactive species may shift the balance between pro- and anti-apoptotic factors such that there is activation of the mitochondrial permeability transition, which would lead to increased cell death in the liver after chronic alcohol consumption. This article will examine the critical role of these reactive species in ethanol-induced liver injury with specific emphasis on how chronic ethanol-associated alterations to mitochondria influence the production of reactive oxygen and nitrogen species and how their production may disrupt hepatic energy conservation in the chronic alcohol abuser.

Alcohol Drinking↗
PubMed1999

Bryostatin 1 enhances paclitaxel-induced mitochondrial dysfunction and apoptosis in human leukemia cells (U937) ectopically expressing Bcl-xL.

The effects of the protein kinase C (PKC) activator and down-regulator bryostatin 1 were examined with respect to paclitaxel-induced apoptosis and antiproliferative activity in human myeloid leukemia cells (U937) displaying enforced expression of the anti-apoptotic protein Bcl-xL. Overexpression of Bcl-xL blocked various aspects of paclitaxel-mediated apoptosis, including caspase-3 activation, degradation of poly(ADP-ribose) polymerase (PARP), loss of mitochondrial membrane potential (Delta Psim), and release of cytochrome c. However, subsequent (but not prior) exposure of paclitaxel-treated U937/Bcl-xL cells (500 nM; 6 h) to bryostatin 1 (10 nM; 15 h) restored the extent of apoptosis, caspase activation, and mitochondrial damage to levels approximating those in paclitaxel-treated empty-vector control cells (U937/Neo). Potentiation of paclitaxel-induced apoptosis by bryostatin 1 in U937/Bcl-xL cells occurred primarily in the G2M cell population, and was associated with alterations in Bcl-xL gel mobility and a reduction in paclitaxel-mediated stimulation of CDK1 activity. Enhancement of paclitaxel-induced apoptosis by bryostatin 1 in Bcl-xL overexpressors was accompanied by a corresponding reduction in clonogenic potential. In contrast to its effects on apoptosis, bryostatin 1 failed to restore paclitaxel-mediated increases in free Bax levels in U937/Bcl-xL cells. Lastly, the actions of bryostatin 1 were mimicked by a pharmacologic inhibitor of the MEK1/MAP kinase pathway (PD98059), but not by SB203580, an inhibitor of p 38 MAP kinase. Moreover, sequential exposure of both U937/Neo or/Bcl-xL cells to paclitaxel followed by bryostatin 1 or PD98059 was associated with a net reduction in MAP kinase activity. Collectively, these findings indicate that protection against paclitaxel-mediated mitochondrial dysfunction and apoptosis in human U937 leukemia cells conferred by Bcl-xL overexpression can be substantially overcome by bryostatin 1 and possibly other agents that interrupt the MAP kinase signal transduction pathway.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Citrobacter rodentium infection causes both mitochondrial dysfunction and intestinal epithelial barrier disruption in vivo: role of mitochondrial associated protein (Map).

Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli are non-invasive attaching/effacing (A/E) bacterial pathogens that infect their host's intestinal epithelium, causing severe diarrhoeal disease. These bacteria utilize a type III secretion apparatus to deliver effector molecules into host cells, subverting cellular function. Mitochondrial associated protein (Map) is a multifunctional effector protein that targets host cell mitochondria and contributes to infection-induced epithelial barrier dysfunction in vitro. Unfortunately, the relevance of these actions to the pathogenesis of EPEC-induced disease is uncertain. Using Citrobacter rodentium, a mouse-adapted A/E bacterium, we found that Map colocalized with host cell mitochondria, and that in vivo infection led to a disruption of mitochondrial morphology in infected colonocytes as assessed by electron microscopy. Histochemical staining for the mitochondrial enzyme succinate dehydrogenase also revealed a significant loss of mitochondrial respiratory function in the infected intestinal epithelium; however, both pathologies were attenuated in mice infected with a Deltamap strain. C. rodentium Map was also implicated in the disruption of epithelial barrier function both in vitro and in vivo. These studies thus advance our understanding of how A/E pathogens subvert host cell functions and cause disease, demonstrating that Map contributes to the functional disruption of the intestinal epithelium during enteric infection by C. rodentium.

Animals↗
PubMed1983

The effects of verapamil on mitochondrial dysfunction associated with coronary reperfusion.

In order to clarify the protective mechanism of verapamil, the following experiment was performed. Twenty-four anesthetized dogs were divided into 3 groups of 8 animals each. In the first, the left anterior descending coronary artery (LAD) was occluded for 15 min; in the second, 5-min reperfusion was done following a 15-min occlusion; in the third, prior to 5-min reperfusion, verapamil (0.4 mg/kg) was infused for 5 min. In each group, heart mitochondria were prepared from the normal and occluded or reperfused areas and their functions were estimated polarographically. The contents of calcium, phospholipids and fatty acids in the mitochondria were also measured by atomic absorption spectrophotometry, Allen's method and gas chromatography, respectively. Although occlusion induced mitochondrial dysfunction, the dysfunction was exacerbated by reperfusion. Occlusion alone did not alter the contents of calcium, phospholipids and fatty acids in mitochondria, while occlusion and subsequent reperfusion increased calcium and fatty acids and decreased phospholipids in mitochondria. Verapamil prevented these reperfusion responses. These results suggest that reperfusion injury of mitochondria is based on the degradation of mitochondrial phospholipids, which is caused by an activation of phospholipase, being triggered by a calcium increase. Verapamil, a calcium antagonist, might protect against reperfusion injury by inhibiting the activation of phospholipase.

Animals↗
PubMed2006

Protective activities of Vaccinium antioxidants with potential relevance to mitochondrial dysfunction and neurotoxicity.

Both the neurotransmitter dopamine (DA) and a neurotoxic metabolite, 6-hydroxy DA, can be oxidized to generate hydrogen peroxide and other reactive species (ROS). ROS promote oxidative stress and have been implicated in dopaminergic neurodegeneration, e.g., Parkinson's disease (PD). There is also evidence for a relation between catecholamine-mediated oxidative damage in dopaminergic neurons and the effects of these neurotransmitters on the redox state of cytochrome c (Cytc). In neurons and other cells, oxidative stress may be enhanced by abnormal release of Cytc and other mitochondrial proteins into the cytoplasm. Cytc release can result in apoptosis; but sub-apoptogenic-threshold release can also occur, and may be highly damaging in the presence of DA metabolites. Loss of mitochondrial membrane integrity, a pathological situation of relevance to several aging-related neurodegenerative disorders including PD, contributes to release of Cytc; and the level of such release is known to be indicative of the extent of mitochondrial dysfunction. In this context, we have used a Cytc-enhanced 6-hydroxy DA oxidation reaction to gauge dietary antioxidant activities. Anthocyanin-rich preparations of Vaccinium species (Vaccinium myrtillus, Vaccinium corymbosum, and Vaccinium oxycoccus) as well as a purified glycosylated anthocyanidin were compared. The most potent inhibition of oxidation was observed with V. myrtillus preparation: 50% inhibition with 7 microM of total anthocyanins. This activity was 1.5-4 times higher than that for the other preparations or for the purified anthocyanin. Ascorbate (Vitamin C), at up to 4-fold higher concentrations, did not result in significant inhibition in this assay. Antioxidant activity in the assay correlated strongly (r2>0.91, P<0.01) with reported Vaccinium content of anthocyanins and total cyanidins, but not quercetin or myricetin. The results provide evidence for the high potency of anthocyanins towards a potentially neurotoxic reaction, and provide a basis for in vivo testing of these flavonoids and their physiological metabolites in the context of neuro- and mitochondrio-protective effects.

Animals↗
PubMed2004

Mitochondrial dysfunction and oxidative damage in parkin-deficient mice.

Loss-of-function mutations in parkin are the predominant cause of familial Parkinson's disease. We previously reported that parkin-/- mice exhibit nigrostriatal deficits in the absence of nigral degeneration. Parkin has been shown to function as an E3 ubiquitin ligase. Loss of parkin function, therefore, has been hypothesized to cause nigral degeneration via an aberrant accumulation of its substrates. Here we employed a proteomic approach to determine whether loss of parkin function results in alterations in abundance and/or modification of proteins in the ventral midbrain of parkin-/- mice. Two-dimensional gel electrophoresis followed by mass spectrometry revealed decreased abundance of a number of proteins involved in mitochondrial function or oxidative stress. Consistent with reductions in several subunits of complexes I and IV, functional assays showed reductions in respiratory capacity of striatal mitochondria isolated from parkin-/- mice. Electron microscopic analysis revealed no gross morphological abnormalities in striatal mitochondria of parkin-/- mice. In addition, parkin-/- mice showed a delayed rate of weight gain, suggesting broader metabolic abnormalities. Accompanying these deficits in mitochondrial function, parkin-/- mice also exhibited decreased levels of proteins involved in protection from oxidative stress. Consistent with these findings, parkin-/- mice showed decreased serum antioxidant capacity and increased protein and lipid peroxidation. The combination of proteomic, genetic, and physiological analyses reveal an essential role for parkin in the regulation of mitochondrial function and provide the first direct evidence of mitochondrial dysfunction and oxidative damage in the absence of nigral degeneration in a genetic mouse model of Parkinson's disease.

Animals↗
PubMed2003

Apoptotic mitochondrial dysfunction induced by benzo(a)pyrene in liver epithelial cells: role of p53 and pHi changes.

How pH(i) changes, more specifically alkalinization, affect the apoptotic cascade has yet to be determined. The aim of the present work was to test the involvement of mitochondria in the apoptotic cascade triggered by benzo(a)pyrene [B(a)P] and to determine the role of pH(i) changes and p53 relative to mitochondria. Our results indicate that B(a)P-induced apoptosis might rely upon a p53-dependent and a pH-sensitive mitochondrial dysfunction.

Animals↗
PubMed2005

T-817MA, a novel neurotrophic agent, improves sodium nitroprusside-induced mitochondrial dysfunction in cortical neurons.

1-{3-[2-(1-Benzothiophen-5-yl)ethoxy]propyl}-3-azetidinol maleate (T-817MA), a novel neurotrophic agent, protects against amyloid-beta peptide- or hydrogen peroxide-induced neuronal death. The exact mechanism of the neuroprotection is not known. This study examines the effects of T-817MA on oxidative stress-induced cytotoxicity in primary rat cortical neurons. Treatment with the NO donor sodium nitoroprusside (SNP) at 300microM decreased cell viability and induced apoptotic cell death. SNP-induced neuronal toxicity was accompanied by a decrease in mitochondrial transmembrane potential without an increase in the expression of CHOP and GRP78 mRNAs, endoplasmic reticulum stress makers. T-817MA at 0.1 and 1microM attenuated the neurotoxicity in a dose-dependent way and the protective effect required pretreatment for more than 8h. T-817MA attenuated SNP-induced decrease in mitochondrial transmembrane potential. In addition, the agent reduced SNP-induced increase in mitochondrial reactive oxygen species (ROS) production. The effects of T-817MA on SNP-induced decrease in cell viability and SNP-induced increase in mitochondrial ROS production were blocked by cycloheximide. These results suggest that T-817MA improves SNP-induced mitochondrial dysfunction in cortical neurons in a newly synthesized protein-mediated mechanism and this effect contributes to its neuroprotective effect.

Animals↗
PubMed2006

Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability: a review.

Radiation-induced genomic instability (RIGI) challenges the long-standing notion that radiation's effects derive solely from nuclear impact. In RIGI it is the unirradiated progeny that can display phenotypic changes at delayed times after irradiation of the parental cell. RIGI might well provide the driving force behind the development of radiation-induced tumorigenesis as most cancer cells even in pre-neoplastic states display multiple genetic alterations. Thus, understanding RIGI may help elucidate the mechanisms underlying radiation-induced carcinogenesis. One characteristic of clones of genetically unstable cells is that many exhibit persistently increased levels of reactive oxygen species (ROS). Furthermore, oxidants enhance and antioxidants diminish radiation-induced instability. However, much about the mechanisms behind the initiation and perpetuation of RIGI remains unknown and we examine the evidence for the hypothesis that oxidative stress and mitochondrial dysfunction may be involved in perpetuating the unstable phenotype in some cell clones surviving ionizing radiation.

Animals↗
PubMed2006

Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome.

Trisomy 21 or Down syndrome (DS) is the most common genetic birth defect associated with mental retardation. The over-expression of genes on chromosome 21, including SOD1 (Cu/Zn superoxide dismutase) and APP (amyloid-beta precursor protein) is believed to underlie the increased oxidative stress and neurodegeneration commonly described in DS. However, a segmental trisomy 16 mouse model for DS, Ts1Cje, has a subset of triplicated human chromosome 21 gene orthologs that exclude APP and SOD1. Here, we report that Ts1Cje brain shows decreases of mitochondrial membrane potential and ATP production, increases of reactive oxygen species, hyperphosphorylation of tau without NFT formation, increase of GSK3beta and JNK/SAPK activities and unaltered AbetaPP metabolism. Our findings suggest that genes on the trisomic Ts1Cje segment other than APP and SOD1 can cause oxidative stress, mitochondrial dysfunction and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS.

Adenosine Triphosphate↗
PubMed2003

Spermine signalling in tobacco: activation of mitogen-activated protein kinases by spermine is mediated through mitochondrial dysfunction.

Polyamines (PAs) play important roles in cell proliferation, growth and environmental stress responses of all living organisms. In this study, we examine whether these compounds act as signal mediators. Spermine (Spm) specifically activated protein kinases of tobacco leaves, which were identified as salicylic acid (SA)-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK), using specific antibodies. Upon Spm treatment, upregulation of WIPK, but not SIPK, was observed. Spm-induced mitogen-activated protein kinases (MAPKs) activation and WIPK upregulation were prevented upon pre-treatment with antioxidants and Ca2+ channel blockers. Additionally, Spm specifically stimulated expression of the alternative oxidase (AOX) gene, which was disrupted by these antioxidants and Ca2+ channel blockers. Bongkrekic acid (BK), an inhibitor of the opening of mitochondrial permeability transition (PT) pores, suppressed MAPKs activation and accumulation of WIPK and AOX mRNA. Our data collectively suggest that Spm causes mitochondrial dysfunction via a signalling pathway in which reactive oxygen species and Ca2+ influx are involved. As a result, the phosphorylation activities of the two MAPK enzymes SIPK and WIPK are stimulated.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
PubMed1989

Effect of 3-(2,2,2-trimethylhydrazinium) propionate, gamma-butyrobetaine hydroxylase inhibitor, on isoproterenol-induced mitochondrial dysfunction.

The present study was designed to investigate whether or not reduction of carnitine content could protect isoproterenol (ISP)-induced myocardial injury using 3-(2,2,2-trimethylhydrazinium) propionate (TMHP), gamma-butyrobetaine hydroxylase inhibitor. Rats were divided into 4 groups; the control group: untreated, the TMHP-1 group: TMHP (100 mg/kg) was administered intraperitoneally, and ISP (10 mg/kg) was administered subcutaneously on the following day, the TMHP-7 group: TMHP (100 mg/kg) for 7 successive days, and ISP (10 mg/kg) on the eighth day, the ISP group: ISP (10 mg/kg) was administered. Rats were cervically dislocated 15 hours after ISP administration, and heart mitochondrial electron-transport activity (NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) were measured enzymatically. Activity of succinate-cytochrome c reductase was not affected significantly by ISP, however, NADH-cytochrome c reductase and cytochrome c oxidase were significantly reduced in the ISP and TMHP groups. Administration with TMHP for 7 successive days lessened the reduction of the activities. Mitochondrial electron-transport system plays an important role in cellular energy transduction. These results suggested that mitochondrial dysfunction induced by ISP is related to carnitine-dependent fatty acid metabolism and that TMHP reduces the myocardial injury.

Animals↗
PubMed2004

LPS-induced apoptosis is dependent upon mitochondrial dysfunction.

Bacterial infection induces apoptotic cell death in human monoblastic U937 cells that have been pretreated with interferon gamma (U937IFN). Apoptosis occurs in a manner that is independent of bacterial virulence proteins. In the present study, we show that lipopolysaccharide (LPS), a membrane constituent of gram-negative bacteria, also induces apoptosis in U937IFN cells. LPS treatment led to the appearance of characteristic markers of apoptosis such as nuclear fragmentation and activation of caspases. While the caspase inhibitor Z-VAD-fmk prevented LPS-induced apoptosis as judged by its inhibition of nuclear fragmentation, it failed to inhibit cytochrome c release and loss of mitochondrial membrane potential. Transfection of peptides containing the BH4 (Bcl-2 homology 4) domain derived from the anti-apoptotic protein Bcl-XL blocked LPS-induced nuclear fragmentation and the limited digestion of PARP. These results suggest that LPS does not require caspase activation to induce mitochondrial dysfunction and that mitochondria play a crucial role in the regulation of LPS-mediated apoptosis in U937IFN cells.

Amino Acid Chloromethyl Ketones↗