FWD: Mitochondrial dysfunction

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just a few items I thought you all might be interested in ....

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This post and the prior one about mito may be forwarded hither and yon.

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*1: *Apoptosis. <javascript:

AL_get(this, 'jour', 'Apoptosis.');> 2008

Feb 26 [Epub ahead of print]

Click here to read

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3055 & itool=AbstractPlus\

-def & uid=18299995 & db=pubmed & url=http://dx.doi.org/10.1007/s10495-008-0182-0

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3055 & itool=AbstractPlus\

-def & uid=18299995 & db=pubmed & url=http://dx.doi.org/10.1007/s10495-008-0182-0>>

Persistent mitochondrial dysfunction and oxidative stress hinder

neuronal cell recovery from reversible proteasome inhibition.

*Papa L*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Papa%20L%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstractPlusDrugs1

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22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstractPlusDrugs1>>,

*Rockwell P*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Rockwell%\

20P%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstractPlusDrugs1

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Rockwell%\

20P%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstractPlusDrugs1>>.

Department of Biological Sciences, Hunter College of The City

University of New York, 695 Park Ave, New York, NY, 10021, USA.

Oxidative stress, proteasome impairment and mitochondrial

dysfunction are implicated as contributors to ageing and

neurodegeneration. Using mouse neuronal cells, we showed previously

that the reversible proteasome inhibitor,

[N-benzyloxycarbonyl-Ile-Glu (O-t-bytul)-Ala-leucinal; (PSI)]

induced excessive reactive oxygen species (ROS) that mediated

mitochondrial damage and a caspase-independent cell death. Herein,

we examined whether this insult persists in neuronal cells

recovering from inhibitor removal over time. Recovery from

proteasome inhibition showed a time and dose-dependent cell death

that was accompanied by ROS overproduction, caspase activation and

mitochondrial membrane permeabilization with the subcellular

relocalizations of the proapoptotic proteins, Bax, cytochrome c and

the apoptosis inducing factor (AIF). Caspase inhibition failed to

promote survival indicating that cell death was caspase-independent.

Treatments with the antioxidant N-acetyl-cysteine (NAC) were needed

to promote survival in cell recovering from mild proteasome

inhibition while overexpression of the antiapoptotic protein Bcl-xL

together with NAC attenuated cell death during recovery from potent

inhibition. Whereas inhibitor removal increased proteasome function,

cells recovering from potent proteasome inhibition showed excessive

levels of ubiquitinated proteins that required the presence of NAC

for their removal. Collectively, these results suggest that the

oxidative stress and mitochondrial inhibition induced by proteasome

inhibition persists to influence neuronal cell survival when

proteasome function is restored.

PMID: 18299995

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*2: *Endocrinology. <javascript:AL_get(this, 'jour', 'Endocrinology.');>

2008 Feb 21 [Epub ahead of print]

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<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=AbstractPlus\

-def & uid=18292191 & db=pubmed & url=http://endo.endojournals.org/cgi/pmidlookup?view\

=long & pmid=18292191

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=AbstractPlus\

-def & uid=18292191 & db=pubmed & url=http://endo.endojournals.org/cgi/pmidlookup?view\

=long & pmid=18292191>>

Progesterone and Estrogen Regulate Oxidative Metabolism in Brain

Mitochondria.

*Irwin RW*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Irwin%20R\

W%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstractPlusDrugs1

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Irwin%20R\

W%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstractPlusDrugs1>>,

*Yao J*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Yao%20J%2\

2%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAb\

stractPlusDrugs1

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2%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAb\

stractPlusDrugs1>>,

*Hamilton R*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Hamilton%\

20R%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstractPlusDrugs1

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*Cadenas E*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Cadenas%2\

0E%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

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*Brinton RD*

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0RD%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

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0RD%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstractPlusDrugs1>>,

*Nilsen J*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Nilsen%20\

J%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstractPlusDrugs1

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J%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstractPlusDrugs1>>.

>From the Department of Pharmacology and Pharmaceutical Sciences,

University of Southern California, Pharmaceutical Sciences Center,

Los Angeles, California, 90033 and the Program in Neuroscience,

University of Southern California, Los Angeles, California, 90033.

The ovarian hormones progesterone and estrogen have well-established

neurotrophic and neuroprotective effects supporting both

reproductive function and cognitive health. More recently, it has

been recognized that these steroids also regulate metabolic

functions sustaining the energetic demands of this neuronal

activation. Underlying this metabolic control is an interpretation

of signals from diverse environmental sources integrated by

receptor-mediated responses converging upon mitochondrial function.

In this study, to determine the effects of progesterone (P4) and

17beta-estradiol (E2) on metabolic control via mitochondrial

function, ovariectomized rats were treated with P4, E2 or E2+P4 and

whole brain mitochondria were isolated for functional assessment.

Brain mitochondria from hormone-treated rats displayed enhanced

functional efficiency and increased metabolic rates. The

hormone-treated mitochondria exhibited increased respiratory

function coupled to increased expression and activity of the

electron transport chain complex IV (cytochrome c oxidase). This

increase respiratory activity was coupled with a decreased rate of

reactive oxygen leak and reduced lipid peroxidation representing a

systematic enhancement of brain mitochondrial efficiency. As such,

ovarian hormone replacement induces mitochondrial alterations in the

central nervous system supporting efficient and balanced

bioenergetics reducing oxidative stress and attenuating endogenous

oxidative damage.

PMID: 18292191

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*1: *J Neural Transm Suppl. <javascript:AL_get(this, 'jour', 'J Neural

Transm Suppl.');> 2007;(72):207-15.

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*Enhanced apoptosis, oxidative stress and mitochondrial dysfunction

in lymphocytes as potential biomarkers for Alzheimer's disease.*

*Leuner K*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Leuner%20\

K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract

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K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract>>,

*Pantel J*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Pantel%20\

J%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract

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J%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract>>,

*Frey C*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Frey%20C%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract

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22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract>>,

*Schindowski K*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Schindows\

ki%20K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pub\

med_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Schindows\

ki%20K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pub\

med_RVAbstract>>,

*Schulz K*

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K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract

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K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract>>,

*Wegat T*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Wegat%20T\

%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV\

Abstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Wegat%20T\

%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV\

Abstract>>,

*Maurer K*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Maurer%20\

K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract

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K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract>>,

*Eckert A*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Eckert%20\

A%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract

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A%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract>>,

*Müller WE*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22M%C3%BCll\

er%20WE%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pu\

bmed_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22M%C3%BCll\

er%20WE%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pu\

bmed_RVAbstract>>.

Zafes, Biocenter, Department of Pharmacology, University of

furt, furt, Germany.

Alzheimer's disease (AD) is the most common progressive

neurodegenerative disease. Today, AD affects millions of people

worldwide and the number of AD cases will increase with increased

life expectancy. The AD brain is marked by severe neurodegeneration

like the loss of synapses and neurons, atrophy and depletion of

neurotransmitter systems in the hippocampus and cerebral cortex.

Recent findings suggest that these pathological changes are causally

induced by mitochondrial dysfunction, increased oxidative stress and

elevated apoptosis. Until now, AD cannot be diagnosed by a valid

clinical method or a biomarker before the disease has progressed so

far that dementia is present. Furthermore, no valid method is

available to determine which patient with mild cognitive impairment

(MCI) will progress to AD. Therefore, a correct diagnosis in the

early stage of AD is not only of importance considering that early

drug treatment is more effective but also that the psychological

burden of the patients and relatives could be decreased. In this

review, we discuss the potential role of elevated apoptosis,

increased oxidative stress and mitochondrial dysfunction as

biomarker for AD in a peripheral cell model, the lymphocytes.

Publication Types:

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17982897 [PubMed - indexed for MEDLINE]

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*2: *J Neurochem. <javascript:AL_get(this, 'jour', 'J Neurochem.');>

2008 Jan;104(2):298-305. Epub 2007 Oct 25.

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*Mitochondrial dysfunction, oxidative stress, regulation of

exocytosis and their relevance to neurodegenerative diseases.*

*Keating DJ*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Keating%2\

0DJ%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Keating%2\

0DJ%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>.

Department of Human Physiology and Centre for Neuroscience, Flinders

University, Adelaide, Australia. damien.keating@...

<mailto:damien.keating%40flinders.edu.au>

A common feature in the early stages of many neurodegenerative

diseases lies in mitochondrial dysfunction, oxidative stress, and

reduced levels of synaptic transmission. Many genes associated with

neurodegenerative diseases are now known to regulate either

mitochondrial function, redox state, or the exocytosis of

neurotransmitters. Mitochondria are the primary source of reactive

oxygen species and ATP and control apoptosis. Mitochondria are

concentrated in synapses and significant alterations to synaptic

mitochondrial localization, number, morphology, or function can be

detrimental to synaptic transmission. Mitochondrial by-products are

capable of regulating various steps of neurotransmission and

mitochondrial dysfunction and oxidative stress occur in the early

stages of many neurodegenerative diseases. This mini-review will

highlight the prospect that mitochondria regulates synaptic

exocytosis by controlling synaptic ATP and reactive oxygen species

levels and that dysfunctional exocytosis caused by mitochondrial

abnormalities may be a common underlying phenomenon in the initial

stages of some human neurodegenerative diseases.

Publication Types:

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'ptyp', 'Research Support, Non-U.S. Gov\'t');>

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17961149 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*3: *J Alzheimers Dis. <javascript:AL_get(this, 'jour', 'J Alzheimers

Dis.');> 2007 Sep;12(2):195-206.

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cle & issn=1387-2877 & volume=12 & issue=2 & spage=195

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*Lipoic acid and N-acetyl cysteine decrease mitochondrial-related

oxidative stress in Alzheimer disease patient fibroblasts.*

*Moreira PI*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Moreira%2\

0PI%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

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0PI%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>,

* PL*

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PL%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

RVAbstract

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PL%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

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*Zhu X*

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2%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAb\

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stract>>,

*Santos MS*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Santos%20\

MS%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Santos%20\

MS%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

RVAbstract>>,

*Oliveira CR*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Oliveira%\

20CR%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Oliveira%\

20CR%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract>>,

* MA*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22%20M\

A%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22%20M\

A%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract>>,

* G*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22%20G\

%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV\

Abstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22%20G\

%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV\

Abstract>>.

Center for Neuroscience and Cell Biology, University of Coimbra,

3004-517 Coimbra, Portugal.

In this study, we evaluated the effect of lipoic acid (LA) and

N-acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal,

N(epsilon)-(carboxymethyl)lysine and heme oxygenase-1] and apoptotic

(caspase 9 and Bax) markers in fibroblasts from patients with

Alzheimer disease (AD) and age-matched and young controls. AD

fibroblasts showed the highest levels of oxidative stress, and the

antioxidants, lipoic acid (1 mM) and/or N-acetyl cysteine (100

microM) exerted a protective effect as evidenced by decreases in

oxidative stress and apoptotic markers. Furthermore, we observed

that the protective effect of LA and NAC was more pronounced when

both agents were present simultaneously. AD-type changes could be

generated in control fibroblasts using N-methylprotoporphyrin to

inhibit cytochrome oxidase assembly indicating that the the

oxidative damage observed was associated with mitochondrial

dysfunction. The effects of N-methylprotoporphyrine were reversed or

attenuated by both lipoic acid and N-acetyl cysteine. These data

suggest mitochondria are important in oxidative damage that occurs

in AD. As such, antioxidant therapies based on lipoic acid and

N-acetyl cysteine supplementation may be promising.

Publication Types:

* Research Support, N.I.H., Extramural <javascript:AL_get(this,

'ptyp', 'Research Support, N.I.H., Extramural');>

* Research Support, Non-U.S. Gov't <javascript:AL_get(this,

'ptyp', 'Research Support, Non-U.S. Gov\'t');>

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17917164 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*4: *Toxicol Sci. <javascript:AL_get(this, 'jour', 'Toxicol Sci.');>

2008 Jan;101(1):81-90. Epub 2007 Oct 4.

Related Articles

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ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17916640 & ord\

inalpos=4 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17916640 & ord\

inalpos=4 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct>>,

Links <javascript:PopUpMenu2_Set(Menu17916640);>

Click here to read

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=Abstract-def\

& uid=17916640 & db=pubmed & url=http://toxsci.oxfordjournals.org/cgi/pmidlookup?view\

=long & pmid=17916640

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=Abstract-def\

& uid=17916640 & db=pubmed & url=http://toxsci.oxfordjournals.org/cgi/pmidlookup?view\

=long & pmid=17916640>>

*The role of mitochondrial and oxidative injury in BDE 47 toxicity

to human fetal liver hematopoietic stem cells.*

*Shao J*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Shao%20J%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Shao%20J%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract>>,

*White CC*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22White%20C\

C%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22White%20C\

C%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_R\

VAbstract>>,

*Dabrowski MJ*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Dabrowski\

%20MJ%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm\

ed_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Dabrowski\

%20MJ%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm\

ed_RVAbstract>>,

*Kavanagh TJ*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Kavanagh%\

20TJ%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Kavanagh%\

20TJ%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract>>,

*Eckert ML*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Eckert%20\

ML%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Eckert%20\

ML%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

RVAbstract>>,

*Gallagher EP*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Gallagher\

%20EP%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm\

ed_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Gallagher\

%20EP%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm\

ed_RVAbstract>>.

Department of Environmental and Occupational Health Sciences,

University of Washington, Seattle, Washington 98105, USA.

The polybrominated diphenyl ethers (PBDEs) are a group of flame

retardants whose residues have markedly increased in the environment

and in human tissues during the last decade. Of the various

congeners, BDE 47 (2,2',4,4'-tetrabromodiphenyl ether) is typically

the predominant congener observed in fish and wildlife samples, as

well as in human tissues. Several studies indicate in utero transfer

of PBDEs during pregnancy with residues accumulating in fetal

tissues, and thus the potential for BDE 47-mediated injury in utero

is of concern. In this study, we examined the mechanisms of BDE

47-mediated injury to primary human fetal liver hematopoietic stem

cells (HSCs), which comprise a large proportion of fetal hepatic

cells and play a key role in hematopoiesis during fetal development.

Incubation of fetal liver HSCs with BDE 47 led to a loss of

mitochondrial membrane potential and the onset of apoptosis. These

effects were observed in the low micromolar range of BDE 47

exposures. At higher concentrations, BDE 47 elicited a loss of

viability, which was accompanied by the generation of reactive

oxygen species and peroxidation of HSC lipids. Preincubation of

fetal liver HSCs with N-acetylcysteine, a glutathione (GSH)

precursor, caused an increase in cellular GSH concentrations,

restored mitochondrial redox status, and ameliorated the toxicity of

BDE 47. BDE 47-mediated cytotoxicity or oxidative injury was not

evident at the lower concentrations (< 1microM). Collectively, these

data support a role for oxidative stress in the cytotoxicity of BDE

47 and indicate that oxidative stress-associated biomarkers may be

useful in assessing the sublethal effects of BDE 47 toxicity in

other models. However, the fact that BDE 47 undergoes a

concentration-dependent accumulation in other primary cells in media

that can underestimate cellular concentrations (W. R. Mundy et al.,

2004, Toxicol. Sci. 82, 164-169) suggests that the HSC cell injury

observed in our study may be of less relevance to human in utero

PBDE exposures.

Publication Types:

* Research Support, N.I.H., Extramural <javascript:AL_get(this,

'ptyp', 'Research Support, N.I.H., Extramural');>

* Research Support, U.S. Gov't, Non-P.H.S.

<javascript:AL_get(this, 'ptyp', 'Research Support, U.S.

Gov\'t, Non-P.H.S.');>

PMID: 17916640 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*5: *J Physiol Biochem. <javascript:AL_get(this, 'jour', 'J Physiol

Biochem.');> 2006 Dec;62(4):303-6.

Related Articles

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17615956 & ord\

inalpos=5 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17615956 & ord\

inalpos=5 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct>>,

Links <javascript:PopUpMenu2_Set(Menu17615956);>

*Mitochondrial oxidative stress and inflammation: an slalom to

obesity and insulin resistance.*

*Martínez JA*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Mart%C3%A\

Dnez%20JA%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.\

Pubmed_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Mart%C3%A\

Dnez%20JA%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.\

Pubmed_RVAbstract>>.

Dept. Physiology and Nutrition. University of Navarra, 31008

Pamplona, Spain. jalfmtz@... <mailto:jalfmtz%40unav.es>

Mitochondria, in addition to energy transformation, play a role in

important metabolic tasks such as apoptosis, cellular proliferation,

heme/steroid synthesis as well as in the cellular redox state

regulation. The mitochondrial phosphorylation process is very

efficient, but a small percentage of electrons may prematurely

reduce oxygen forming toxic free radicals potentially impairing the

mitochondria function. Furthermore, under certain conditions,

protons can reenter the mitochondrial matrix through different

uncoupling proteins (UCPs), affecting the control of free radicals

production by mitochondria. Disorders of the mitochondrial electron

transport chain, overgeneration of reactive oxygen species (ROS) and

lipoperoxides or impairments in antioxidant defenses have been

reported in situations of obesity and type-2 diabetes. On the other

hand, obesity has been associated to a low degree pro-inflammatory

state, in which impairments in the oxidative stress and antioxidant

mechanism could be involved. Indeed, reactive oxygen species have

been attributed a causal role in multiple forms of insulin

resistance. The scientific evidence highlights the importance of

investigating the relationships between oxidative stress and

inflammation with obesity/diabetes onset and underlines the need to

study in mitochondria from different tissues, the interactions of

such factors either as a cause or consequence of obesity and insulin

resistance.

Publication Types:

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17615956 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*6: *Pharmacol Rep. <javascript:AL_get(this, 'jour', 'Pharmacol

Rep.');>

2007 Mar-Apr;59(2):206-15.

Related Articles

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ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17556799 & ord\

inalpos=6 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17556799 & ord\

inalpos=6 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct>>,

Links <javascript:PopUpMenu2_Set(Menu17556799);>

Click here to read

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=4150 & itool=Abstract-def\

& uid=17556799 & db=pubmed & url=http://www.if-pan.krakow.pl/pjp/pdf/2007/2_206.pdf

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=4150 & itool=Abstract-def\

& uid=17556799 & db=pubmed & url=http://www.if-pan.krakow.pl/pjp/pdf/2007/2_206.pdf>>

*Toxicity of pyrimidine derivatives under oxidative stress

conditions: chemiluminescence-based assays in systems containing

erythrocytes, mitochondria or blood plasma.*

*Sajewicz W*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Sajewicz%\

20W%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Sajewicz%\

20W%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>.

Department of Toxicology, Medical University, Traugutta 57/59, PL

54-417 Wroc?aw, Poland. sajewicz@...

<mailto:sajewicz%40tox.am.wroc.pl>

Participation of mono-, di-, and tricyclic pyrimidine derivatives in

free radical processes was investigated with the use of

luminol-enhanced chemiluminescence in measurements performed in

vitro in systems containing erythrocytes, erythrocyte lysate,

erythrocyte membranes, mitochondria, mitoplasts or blood plasma. The

free radical processes were induced in the investigated systems by

tert -butyl hydroperoxide ( t -BuOOH) or

2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). Amongst the

examined compounds, only derivatives containing the thiol

substituent were found to modify the course of chemiluminescence.

Effects of both amplification and inhibition of light emission were

observed to depend on the structure of a derivative and on the type

of a biological (experimental) system. The light emission-amplifying

activity was found to be characteristic of the system containing

erythrocytes. The results of the investigations point out that the

pyrimidine thio-derivatives prolonged the oxidative stress through

some interactions mainly with (oxy)hemoglobin, which was related

with specific toxicity against erythrocytes. Model investigations in

the proposed experimental systems can serve as a useful tool at

early stages of the drug discovery process when compounds involved

in the interactions connected with the oxidative stress are being

selected. On the other hand, this method allows to study mechanisms

of the toxic action of xenobiotics on cells (erythrocytes) and

organelles (mitochondria), strongly implicated in the free radical

generation, and to examine the role of the extracellular liquid

(plasma).

Publication Types:

* Research Support, Non-U.S. Gov't <javascript:AL_get(this,

'ptyp', 'Research Support, Non-U.S. Gov\'t');>

PMID: 17556799 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*7: *Exp Biol Med (Maywood). <javascript:AL_get(this, 'jour', 'Exp Biol

Med (Maywood).');> 2007 May;232(5):592-606.

Related Articles

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ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17463155 & ord\

inalpos=7 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17463155 & ord\

inalpos=7 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct>>,

Links <javascript:PopUpMenu2_Set(Menu17463155);>

Click here to read

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=Abstract-def\

& uid=17463155 & db=pubmed & url=http://www.ebmonline.org/cgi/pmidlookup?view=long & pm\

id=17463155

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=Abstract-def\

& uid=17463155 & db=pubmed & url=http://www.ebmonline.org/cgi/pmidlookup?view=long & pm\

id=17463155>>

*Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging.*

*Lee HC*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Lee%20HC%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Lee%20HC%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract>>,

*Wei YH*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Wei%20YH%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Wei%20YH%\

22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVA\

bstract>>.

Department of Pharmacology, National Yang-Ming University, Taipei,

Taiwan, Republic of China.

A wide spectrum of alterations in mitochondria and mitochondrial DNA

(mtDNA) with aging has been observed in animals and humans. These

include (i) decline in mitochondrial respiratory function; (ii)

increase in mitochondrial production of reactive oxygen species

(ROS) and the extent of oxidative damage to DNA, proteins, and

lipids; (iii) accumulation of point mutations and large-scale

deletions of mtDNA; and (iv) enhanced apoptosis. Recent studies have

provided abundant evidence to substantiate the importance of

mitochondrial production of ROS in aging. On the other hand, somatic

mtDNA mutations can cause premature aging without increasing ROS

production. In this review, we focus on the roles that ROS play in

the aging-associated decline of mitochondrial respiratory function,

accumulation of mtDNA mutations, apoptosis, and alteration of gene

expression profiles. Taking these findings together, we suggest that

mitochondrial dysfunction, enhanced oxidative stress, subsequent

accumulation of mtDNA mutations, altered expression of a few

clusters of genes, and apoptosis are important contributors to human

aging.

Publication Types:

* Research Support, Non-U.S. Gov't <javascript:AL_get(this,

'ptyp', 'Research Support, Non-U.S. Gov\'t');>

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17463155 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*8: *J Neurol Sci. <javascript:AL_get(this, 'jour', 'J Neurol Sci.');>

2007 Jun 15;257(1-2):221-39. Epub 2007 Apr 25.

Related Articles

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ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17462670 & ord\

inalpos=8 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17462670 & ord\

inalpos=8 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstra\

ct>>,

Links <javascript:PopUpMenu2_Set(Menu17462670);>

Click here to read

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048 & itool=Abstract-def\

& uid=17462670 & db=pubmed & url=http://linkinghub.elsevier.com/retrieve/pii/S0022-51\

0X%2807%2900065-2

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048 & itool=Abstract-def\

& uid=17462670 & db=pubmed & url=http://linkinghub.elsevier.com/retrieve/pii/S0022-51\

0X%2807%2900065-2>>

*Mitochondria, metabolic disturbances, oxidative stress and the

kynurenine system, with focus on neurodegenerative disorders.*

*Sas K*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Sas%20K%2\

2%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAb\

stract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Sas%20K%2\

2%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAb\

stract>>,

*Robotka H*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Robotka%2\

0H%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Robotka%2\

0H%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_\

RVAbstract>>,

*Toldi J*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Toldi%20J\

%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV\

Abstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Toldi%20J\

%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RV\

Abstract>>,

*Vécsei L*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22V%C3%A9cs\

ei%20L%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pub\

med_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22V%C3%A9cs\

ei%20L%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pub\

med_RVAbstract>>.

Department of Neurology, University of Szeged, POB 427, H-6701

Szeged, Hungary.

The mitochondria have several important functions in the cell. A

mitochondrial dysfunction causes an abatement in ATP production,

oxidative damage and the induction of apoptosis, all of which are

involved in the pathogenesis of numerous disorders. This review

focuses on mitochondrial dysfunctions and discusses their

consequences and potential roles in the pathomechanism of

neurodegenerative disorders. Other pathogenetic factors are also

briefly surveyed. The second part of the review deals with the

kynurenine metabolic pathway, its alterations and their potential

association with cellular energy impairment in certain

neurodegenerative diseases. During energy production, most of the

O(2) consumed by the mitochondria is reduced fully to water, but

1-2% of the O(2) is reduced incompletely to give the superoxide

anion (O(2)(-)). If the function of one or more respiratory chain

complexes is impaired for any reason, the enhanced production of

free radicals further worsens the mitochondrial function by causing

oxidative damage to macromolecules, and by opening the mitochondrial

permeability transition pores thereby inducing apoptosis. These

high-conductance pores offer a pathway which can open in response to

certain stimuli, leading to the induction of the cells' own suicide

program. This program plays an essential role in regulating growth

and development, in the differentiation of immune cells, and in the

elimination of abnormal cells from the organism. Both failure and

exaggeration of apoptosis in a human body can lead to disease. The

increasing amount of superoxide anions can react with nitric oxide

to yield the highly toxic peroxynitrite anion, which can destroy

cellular macromolecules. The roles of oxidative, nitrative and

nitrosative damage are discussed. Senescence is accompanied by a

higher degree of reactive oxygen species production, and by

diminished functions of the endoplasmic reticulum and the proteasome

system, which are responsible for maintenance of the normal protein

homeostasis of the cell. In the event of a dysfunction of the

endoplasmic reticulum, unfolded proteins aggregate in it, forming

potentially toxic deposits which tend to be resistant to

degradation. Cells possess adaptive mechanisms with which to avoid

the accumulation of incorrectly folded proteins. These involve

molecular chaperones that fold proteins correctly, and the ubiquitin

proteasome system which degrades misfolded, unwanted proteins. Both

the endoplasmic reticulum and the ubiquitin proteasome system

fulfill cellular protein quality control functions. The kynurenine

system: Tryptophan is metabolized via several pathways, the main one

being the kynurenine pathway. A central compound of the pathway is

kynurenine (KYN), which can be metabolized in two separate ways: one

branch furnishing kynurenic acid, and the other 3-hydroxykynurenine

and quinolinic acid, the precursors of NAD. An important feature of

kynurenic acid is the fact that it is one of the few known

endogenous excitatory amino acid receptor blockers with a broad

spectrum of antagonistic properties in supraphysiological

concentrations. One of its recently confirmed sites of action is the

alpha7-nicotinic acetylcholine receptor and interestingly, a more

recently identified one is a higher affinity positive modulatory

binding site at the AMPA receptor. Kynurenic acid has proven to be

neuroprotective in several experimental settings. On the other hand,

quinolinic acid is a specific agonist at the N-methyl-d-aspartate

receptors, and a potent neurotoxin with an additional and marked

free radical-producing property. There are a number of

neurodegenerative disorders whose pathogenesis has been demonstrated

to involve multiple imbalances of the kynurenine pathway metabolism.

These changes may disturb normal brain function and can add to the

pathomechanisms of the diseases. In certain disorders, there is a

quinolinic acid overproduction, while in others the alterations in

brain kynurenic acid levels are more pronounced. A more precise

knowledge of these alterations yields a basis for getting better

therapeutic possibilities. The last part of the review discusses

metabolic disturbances and changes in the kynurenine metabolic

pathway in Parkinson's, Alzheimer's and Huntington's diseases.

Publication Types:

* Research Support, Non-U.S. Gov't <javascript:AL_get(this,

'ptyp', 'Research Support, Non-U.S. Gov\'t');>

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17462670 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*9: *Apoptosis. <javascript:AL_get(this, 'jour', 'Apoptosis.');> 2007

May;12(5):913-22.

Related Articles

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ct

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17453160 & ord\

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ct>>,

Links <javascript:PopUpMenu2_Set(Menu17453160);>

Click here to read

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3055 & itool=Abstract-def\

& uid=17453160 & db=pubmed & url=http://dx.doi.org/10.1007/s10495-007-0756-2

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3055 & itool=Abstract-def\

& uid=17453160 & db=pubmed & url=http://dx.doi.org/10.1007/s10495-007-0756-2>>

*Mitochondria, oxidative stress and cell death.*

*Ott M*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Ott%20M%2\

2%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAb\

stract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Ott%20M%2\

2%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAb\

stract>>,

*Gogvadze V*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Gogvadze%\

20V%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Gogvadze%\

20V%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>,

*Orrenius S*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Orrenius%\

20S%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Orrenius%\

20S%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>,

*Zhivotovsky B*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Zhivotovs\

ky%20B%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pub\

med_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Zhivotovs\

ky%20B%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pub\

med_RVAbstract>>.

Institute of Environmental Medicine, Karolinska Institutet, S-171 77

Stockholm, Sweden.

In addition to the well-established role of the mitochondria in

energy metabolism, regulation of cell death has recently emerged as

a second major function of these organelles. This, in turn, seems to

be intimately linked to their role as the major intracellular source

of reactive oxygen species (ROS), which are mainly generated at

Complex I and III of the respiratory chain. Excessive ROS production

can lead to oxidation of macromolecules and has been implicated in

mtDNA mutations, ageing, and cell death. Mitochondria-generated ROS

play an important role in the release of cytochrome c and other

pro-apoptotic proteins, which can trigger caspase activation and

apoptosis. Cytochrome c release occurs by a two-step process that is

initiated by the dissociation of the hemoprotein from its binding to

cardiolipin, which anchors it to the inner mitochondrial membrane.

Oxidation of cardiolipin reduces cytochrome c binding and results in

an increased level of " free " cytochrome c in the intermembrane

space. Conversely, mitochondrial antioxidant enzymes protect from

apoptosis. Hence, there is accumulating evidence supporting a direct

link between mitochondria, oxidative stress and cell death.

Publication Types:

* Research Support, Non-U.S. Gov't <javascript:AL_get(this,

'ptyp', 'Research Support, Non-U.S. Gov\'t');>

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17453160 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*10: *Mol Cell Biol. <javascript:AL_get(this, 'jour', 'Mol Cell

Biol.');> 2007 May;27(10):3625-39. Epub 2007 Mar 5.

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inalpos=10 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstr\

act

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17339328 & ord\

inalpos=10 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstr\

act>>,

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<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=Abstract-def\

& uid=17339328 & db=pubmed & url=http://mcb.asm.org/cgi/pmidlookup?view=long & pmid=173\

39328

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051 & itool=Abstract-def\

& uid=17339328 & db=pubmed & url=http://mcb.asm.org/cgi/pmidlookup?view=long & pmid=173\

39328>>

Click here to read

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3494 & itool=Abstract-non\

def & uid=17339328 & db=pubmed & url=http://www.pubmedcentral.nih.gov/articlerender.fc\

gi?tool=pubmed & pubmedid=17339328

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3494 & itool=Abstract-non\

def & uid=17339328 & db=pubmed & url=http://www.pubmedcentral.nih.gov/articlerender.fc\

gi?tool=pubmed & pubmedid=17339328>>

*Novel role for mitochondria: protein kinase Ctheta-dependent

oxidative signaling organelles in activation-induced T-cell death.*

*Kaminski M*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Kaminski%\

20M%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Kaminski%\

20M%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>,

*Kiessling M*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Kiessling\

%20M%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Kiessling\

%20M%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract>>,

*Süss D*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22S%C3%BCss\

%20D%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22S%C3%BCss\

%20D%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract>>,

*Krammer PH*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Krammer%2\

0PH%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Krammer%2\

0PH%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>,

*Gülow K*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22G%C3%BClo\

w%20K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm\

ed_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22G%C3%BClo\

w%20K%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm\

ed_RVAbstract>>.

Tumor Immunology Program, German Cancer Research Center (DKFZ), Im

Neuenheimer Feld 280, 69120 Heidelberg, Germany.

Reactive oxygen species (ROS) play a key role in regulation of

activation-induced T-cell death (AICD) by induction of CD95L

expression. However, the molecular source and the signaling steps

necessary for ROS production are largely unknown. Here, we show that

the proximal T-cell receptor-signaling machinery, including ZAP70

(zeta chain-associated protein kinase 70), LAT (linker of activated

T cells), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa),

PLCgamma1 (phospholipase Cgamma1), and PKCtheta (protein kinase

Ctheta), are crucial for ROS production. PKCtheta is translocated to

the mitochondria. By using cells depleted of mitochondrial DNA, we

identified the mitochondria as the source of activation-induced ROS.

Inhibition of mitochondrial electron transport complex I assembly by

small interfering RNA (siRNA)-mediated knockdown of the chaperone

NDUFAF1 resulted in a block of ROS production. Complex I-derived ROS

are converted into a hydrogen peroxide signal by the mitochondrial

superoxide dismutase. This signal is essential for CD95L expression,

as inhibition of complex I assembly by NDUFAF1-specific siRNA

prevents AICD. Similar results were obtained when metformin, an

antidiabetic drug and mild complex I inhibitor, was used. Thus, we

demonstrate for the first time that PKCtheta-dependent ROS

generation by mitochondrial complex I is essential for AICD.

Publication Types:

* Research Support, Non-U.S. Gov't <javascript:AL_get(this,

'ptyp', 'Research Support, Non-U.S. Gov\'t');>

PMID: 17339328 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

*11: *Neuroscience. <javascript:AL_get(this, 'jour', 'Neuroscience.');>

2007 Apr 14;145(4):1233-48. Epub 2007 Feb 14.

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inalpos=11 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstr\

act

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & DbFrom=pubmed & Cmd=Link & LinkN\

ame=pubmed_pubmed & LinkReadableName=Related%20Articles & IdsFromResult=17303344 & ord\

inalpos=11 & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstr\

act>>,

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<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048 & itool=Abstract-def\

& uid=17303344 & db=pubmed & url=http://linkinghub.elsevier.com/retrieve/pii/S0306-45\

22%2806%2901433-3

<http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3048 & itool=Abstract-def\

& uid=17303344 & db=pubmed & url=http://linkinghub.elsevier.com/retrieve/pii/S0306-45\

22%2806%2901433-3>>

*Oxidative stress and mitochondrial dysfunction in neurodegenerative

diseases.*

*Trushina E*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Trushina%\

20E%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22Trushina%\

20E%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed\

_RVAbstract>>,

*McMurray CT*

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22McMurray%\

20CT%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract

<http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed & Cmd=Search & Term=%22McMurray%\

20CT%22%5BAuthor%5D & itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubme\

d_RVAbstract>>.

Department of Molecular Pharmacology and Experimental Therapeutics,

Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

In recent years, it has become increasingly clear that mitochondrial

dysfunction and oxidative damage are major contributors to neuronal

loss. Free radicals, typically generated from mitochondrial

respiration, cause oxidative damage of nucleic acids, lipids,

carbohydrates and proteins. Despite enormous amount of effort,

however, the mechanism by which oxidative damage causes neuronal

death is not well understood. Emerging data from a number of

neurodegenerative diseases suggest that there may be common features

of toxicity that are related to oxidative damage. In this review,

while focusing on Huntington's disease (HD), we discuss similarities

among HD, Friedreich ataxia and xeroderma pigmentosum, which provide

insight into shared mechanisms of neuronal death.

Publication Types:

* Research Support, N.I.H., Extramural <javascript:AL_get(this,

'ptyp', 'Research Support, N.I.H., Extramural');>

* Research Support, Non-U.S. Gov't <javascript:AL_get(this,

'ptyp', 'Research Support, Non-U.S. Gov\'t');>

* Review <javascript:AL_get(this, 'ptyp', 'Review');>

PMID: 17303344