Resources > MitoNews > Archives > Volume 01, Issue 03 - March, 2005

Volume 01, Issue 03 - March, 2005




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MitoNews
Mitochondrial Research Bulletin

Published by:
MitoSciences
Advancing Vital Discoveries in Mitochondrial Research
http://www.mitosciences.com

Edited & Moderated by:
Dr. Roderick Capaldi
rcapaldi@mitosciences.com

Volume 01, Issue 03 - March 24, 2005
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In This Issue...


RECENT RESEARCH
1. Release of cytochrome c is not all or none but a measured
response to mitochondrial dysfunction

2. Mitochondria and Niemann Pick disease

3. Amyloid beta peptide reacts with mitochondrial alcohol
dehydrogenase in Alzheimers Disease

4. Insulin to treat Alzheimers disease?

5. Proteomics of the mitochondrial fraction from primary
neuron cultures treated with Abeta; the connection to ATP
production.

6. Mitochondrial dysfunction in hepatitis C

7. Watching a mitochondrion in action.

8. SCO1; a copper chaperone or NOT

9. Aminoglycoside toxicity and mitochondrial genetics

10. Prostaglandin interaction with mitochondrial complex I

11. Treat depression, alter mitochondria, kill cancer.

12. Control of cytochrome c oxidase by phosphorylation;
a proteomics study.

13. Mitochondrial DNA mutations in bipolar disorder and
schizophrenia

14. More on mitochondrial dysfunction and bipolar disorder.

15. Complex I dysfunction related to Parkinsons disease and
Chinese herbal remedies.



ANNOUNCEMENT

ONE WEEK INTENSIVE LABORATORY WORKSHOP IN
TECHNIQUES FOR MITOCHONDRIAL RESEARCH
  

....................................................................................................
RECENT RESEARCH
....................................................................................................

1. Release of cytochrome c is not all or none but a measured
response to mitochondrial dysfunction

The prevailing view is that cytochrome c release to induce
apoptosis is an all or none effect. In the paper below contrary
evidence is presented that shows a graded response to
mitochondria functional deficit. In this study OXPHOS activity
was progressively diminished by the complex I inhibitor
rotenone.  This resulted in a proportional cytochrome c release
from rat brain mitochondria mediated by the bax/porin
interaction mechanism rather than by membrane rupture.
Most interestingly, cytochrome c release was subthreshold for
the induction of apoptosis.

CLAYTON.R, CLARK.JB & SHARPE.M. JNeurochem 92
840-9 (2005)



2. Mitochondria and Niemann Pick disease

Until relatively recently, dogma had it that mitochondria do not
contain cholesterol. Now we know that mitochondrial
membranes both contain this lipid and that the organelle
metabolizes it. The work of Yu et al below shows that the
amount of cholesterol is significantly elevated within
mitochondrial membranes of Niemann Pick Disease C1 type
(NPC1) mouse brain and neurons Also, there is a decreased
ATP synthase activity and reduced mitochondrial membrane
potential. Reducing the level of cholesterol with the drug
methyl-SS-cyclodextrin restored ATP synthase activity. 
The authors argue that ATP deficiency induced by altered
cholesterol metabolism in mitochondria explains the neuronal
impairment in NPC1 disease.

YU.W, GONG.JS, KO.M, GARVER.WS, YANAGISAWA.K &
MICHIKAWA. M. J BIOL CHEM 280. 11731-9 (2005)



3. Amyloid beta peptide reacts with mitochondrial alcohol
dehydrogenase in Alzheimers Disease

In the February issue of this newsletter a paper was reviewed
in which the direct interaction of Abeta with cytochrome c
oxidase was reported. Recently 3 more papers describing
Abeta toxicity via mitochondria have appeared. In the paper
referenced below the authors examined the link between
Abeta toxicity and its interaction with the mitochondrial alcohol
dehydrogenase (ABAD). Neurons were cultured from
transgenic mice with targeted overexpression of the mutant
form of Abeta, with overexpression of ABAD, or with
overexpression of both protein in the same cells. Neurons
from mice with both proteins overexpressed displayed high
levels of generation of H2O2 and superoxide, decreased
ATP and subsequent apoptosis of these cells. The generation
of reactive oxygen species was associated with decreased
cytochrome c oxidase activity. Cells from mice with targeted
expression of either protein alone did not show altered
mitochondrial properties. The authors argue that
ABAD-induced oxidative stress is a key part of cellular
dysfunction in Alzheimers disease.

TAKUMA.K,YAO.J,HUANG.J,XU.H,CHEN.X,LUDDY.J,
TRILLAT.AC,STERN.DM,ARANCIO.O & YAN.SS.
FASEB J. published Jan21 and available online (2005)



4. Insulin to treat Alzheimers disease?

In the study below the authors examine the effect of Abeta
on brain mitochondria from both untreated and insulin
treated streptozotocin (STZ) diabetic rats. STZ induced
diabetes decreased mitochondrial CoQ levels, reduced
ATPase activity and lowered the capacity of the organelle
to accumulate Ca++ compared to control rats or STZ rats
treated with insulin. The presence of Abeta altered
mitochondrial function and increased H2O2 production in
STZ diabetic rats, an effect not seen in the insulin treated
animals. The authors conclude that insulin prevents Abeta
induced decline of OXPHOS efficiency thereby reducing
oxidative stress.

MOREIRA.PI ,SANTOS.MS, SENA.C, SEICA.R &
OLIVEIRA.CR.  NEUOBIOL DIS. 18. 628-37 (2005)



5. Proteomics of the mitochondrial fraction from primary
neuron cultures treated with Abeta; the connection to ATP
production.

In the study below proteomic analysis involving isotype-coded
affinity tagging and mass spectroscopy (2D-LC/MS/MS) was
used to identify and quantitate cysteine -containing proteins
before and after Abeta treatment. The observed elevation
in amounts of energy transducing and ATP mobilizing enzymes
led the authors to propose that there is an increased synthesis
of proteins essential for ATP production in an attempt to
maintain metabolic function in cells undergoing Abeta mediated
apoptosis.

LOVELL.MA, XIONG.S, MARKESBERY.WR & LYNN.BC.
Neurochem.Res. 30. 113-22 (2005).



6. Mitochondrial dysfunction in hepatitis C

The interesting review below, focuses on mitochondrial
effects of the hepatitis C virus. The core protein of this virus
has been shown to localize to mitochondria and reside at
points of contact between the outer membrane of this organelle
and the endoplasmic reticulum.. It¹s expression causes
inhibition of complex I with resulting increased levels of reactive
oxygen species. Possible mechanisms of this effect are
covered, including direct interaction with complex I and/or
indirect effects mediated by changes in mitochondrial calcium. 
The authors posit that antioxidant treatments will be beneficial
for patients with chronic hepatitis C.

KORENAGA.M, OKUDA.M, OTANI.K, WANG.T, LI.Y &
WEINMAN. SA. J. Clin. Gastroenterol. 39. S162-6 (2005)



7. Watching a mitochondrion in action.

It is to be expected that delta psi in mitochondria depends on
organellar functioning. In the paper referenced below,
spontaneous fluctuations of delta psi have been measured
from single mitochondria by time resolved fluorescence
microscopy. Various substrates for the electron transport
chain were used to induce polarization of the inner membrane.
This initial polarization was seen to be followed by repeated
cycles of rapid depolarization and repolarization These rapid
fluctuations were not related to the permeability transition
pore as they were not seen when mitochondria were polarized
by K+ efflux from the matrix and were not blocked by
cyclosporin A or by bonkrekic acid. ADP decreased the
frequency of the depolarizations, leading the authors to
conclude that the observed fluctuations in delta psi follow
proton pumping in the organelle.

HATTORI. T, WATANABE.K, UECHI.Y,YOSHIOKA.H &
OHTA.Y. Biophys.J. 88. 2340-9 (2005)



8. SCO1; a copper chaperone or NOT

Many crystallographers are moving away from determining
the structures of small globular proteins, which are now often
thought of as passé, to work on the large multiprotein
complexes (which has impacted mitochondrial research
favorably). Nevertherless, the structures of small proteins
can still provide surprises, as the paper reviewed below
attests. It had generally been believed that SCO1, an
assembly factor for cytochrome c oxidase, is a copper
chaperone. However, the X ray structure reveals a protein
similar to redox active proteins such as the thioredoxins
and peroxyredoxins with the putative copper binding
ligands of SCO 1 located at conserved positions in the
catalytic site of the the two classes of redox enzymes.
Arguments that Sco1 is a mitochondrial redox signaling
molecule include the enhanced sensitive to H2O2 of
null mutants for the protein in yeast, and the location
of pathogenic mutations away from the copper binding
region and in sites of likely protein-protein interaction.

WILLIAMS. JC, SUE.C, BANTING.GS, YANG.H,
GLERUM.DM, HENDRICKSON.WA & SCHON.EA.
J. Biol. Chem published Jan19 available online (2005)



9. Aminoglycoside toxicity and mitochondrial genetics

One of the earliest described drug toxicities due to
mitochondrial dysfunction is the ototoxicity of aminoglycosides. 
In the review referenced below, the author describes the role
of the mitochondrial12S ribosomal RNA gene in the condition. 
Mutations in this gene are considered to predispose patients
to aminoglycoside ototoxicity. Therefore, screening of patients
for drug sensitivity prior to prescribing is possible and would
be useful but this is not often done.

FISCHEL-GHODSIAN.N. Pharmacogenomics 6. 27-36. (2005)



10. Prostaglandin interaction with mitochondrial complex I

The compound 15d-Prostaglandin J2 acts in inflammation,
apoptosis and cell growth through its interaction with a number
of proteins including the transcription factors PPAR gamma
and NF-kappaB. In the study below evidence is provided that
this prostaglandin also reacts with NADH-ubiquinone
oxidoreductase (Complex I) to inhibit the complex while at
the same time increasing the rate of reactive oxygen species
generation. This inhibition was abolished by dithiothreitol
suggesting that the reaction is a direct one with the protein
complex.

MARTINEZ.B, PEREZ-CASTILLO.A & SANTOS.A.
J. Lipid Res. 46. 736-43 (2005)



11. Treat depression, alter mitochondria, kill cancer.

In the study below the authors show that the anti-depressant
chlorimipramine kills glioma cells in vitro in a mechanism
involving increased caspase 3 activity when oxygen utilization
is inhibited. Addition of the drug to isolated rat mitochondria
inhibited mitochondrial complex III activity with reduced
membrane potential and changes in morphology of the
organelle. The authors argue that chloimipramine may be
an effective, non-toxic therapeutic with strong selectivity for
cancer cells over normal cells because of their different
mitochondrial functioning.

DALEY.E, WILKIE.D, LOESCH.A, HARGREAVES.IP,
KENDALL.DA, PILKINGTON.GJ & BATES. TE.
Biochem. Biophys Res. Commun. 328. 623-32 (2005)



12. Control of cytochrome c oxidase by phosphorylation;
a proteomics study.

The work of Kadenbach and colleagues has focused attention
on the regulation of cytochrome c oxidase. In the paper
below, direct evidence of a cAMP dependent phosphorylation
of cytochrome c oxidase is presented using proteomics.
The site of this phosphorylation was located in bovine enzyme
by mass spectrometry as tyrosine 304 of subunit I. Tyrosine
304 is in the interface between the monomers of the enzyme
dimer. Subunit I phosphorylation led to a decreased Vmax
of the oxidase and increased Km of cytochrome c binding. 
Following on from these findings the authors induced the
starvation signal in human HepG2 cells and cow liver tissue
with glucagon which signals through cAMP and examined
the effect on cytochome c oxidase functioning. Glucagon
treatment led to cytochrome c oxidase inactivation. The
authors link the two sets of observations and suggest a
mechanism for the effect of phosphorylation on enzyme
functioning.

LEE.I, SALOMON.AR, FICARRO.S, MATHES.I,
LOTTSPEICH.F, GROSSMAN. LI & HUTTERMANN M. 
J Biol. Chem.. 280. 6094-100. (2005)



13. Mitochondrial DNA mutations in bipolar disorder and
schizophrenia

The involvement of mitochondrial dysfunction in a number
of behavioral brain disorders is being described with increasing
frequency. Epidemiological studies have identified a link
between the A3243G mtDNA mutation and both bipolar disorder
and schizophrenia (in addition to diseases such as MELAS). 
In the study below the authors linked the presence of increased
levels of mitochondrial leucyl tRNA synthetase (LARS2) with
the A3243G mutation in transmitochondrial cybrids carrying
this tRNA mutation. This same upregulation of LARS2 was
detected in the postmortem brain of 2 patients with bipolar
disorder and one with schizophrenia. The authors argue that
upregulation of LARS2 is a hallmark of the A3243G mutation
and that accumulation of this mutation has a pathogenic role
in the above mental diseases.

MUNAKATA.K, IWAMOTO.K, BUNDO.M & KATO.T. 
Biol. Psychiatry 57. 525-32 (2005)



14. More on mitochondrial dysfunction and bipolar disorder.

Kato and colleagues have previously reported a linkage
between the mitochondrial complex I subunit NDUFV2
gene and bipolar disorder. A decrease in the mRNA
expression for this gene was found in patients with bipolar
disorder when compared to controls. In this new study
below, the same group examined the expression of the
genes of other nuclear encoded mitochondrial proteins
located on chromosome regions that have been linked
with bipolar disorder. In all they did real time quantitative
reverse PCR of the genes for 5 subunits of complex I, 3
subunits of complex IV and 4 mitochondrial transcription
related genes using lymphoblastoid cells derived from 21
patients with bipolar disorder and 11 controls. Decreased
expression of all of the complex I genes was observed
while there was no alteration of 2 of the 3 complex IV genes
or any of the transcription factor genes.

WASHIZUKA.S, KAKIUCHI.C, MORI.K, TAJIMA & KATO.T. 
Bipolar Disord. 7. 146-52 (2005).



15. Complex I dysfunction related to Parkinsons disease and
Chinese herbal remedies.

It has been shown that the 1- methyl-4-phenylpyridinium ion
(MPP+) elicits a Parkinsons disease-like syndrome with
elevation of reactive oxygen species through its interaction
with complex I. In the study below the authors examined
the protective effect of salvianic acid A (SA) isolated from the
Chinese herbal medicine Salvia miltorrhiza on MPP+ induced
cytotoxicity in the human neuroblasoma SH-SY5Y cell line. 
MPP+ causes elevated ROS production, relocation of Bax
to mitochondria, and activation of caspase in this cell line.
  All of these effects could be prevented by addition of SA. 
The authors propose the use of SA as a therapy for
progressive neurodegenerative diseases such as Parkinsons
disease.

WANG.XJ & XU. JX. J.Neurosci Res. 51. 129-138 (2005)



....................................................................................................
ANNOUNCEMENT
....................................................................................................

ONE WEEK INTENSIVE LABORATORY WORKSHOP IN
TECHNIQUES FOR MITOCHONDRIAL RESEARCH

A number of investigators have requested assistance in
establishing in their own laboratories the novel protocols
being developed by MitoSciences for mitochondrial research. 

In response we recently held a 5-day intensive
workshop/laboratory training in our newly remodeled facility
in Eugene Oregon. This was a great success, and so
appreciated by the participants, that we have decided to
offer the workshop on a more regular basis, possibly bi-monthly.
 
Briefly, we train participants in mitochondrial isolation from
tissue and cell culture material, in SDSPAGE, blue native gel
electrophoresis and Western blotting, in immunocytochemistry
and in immunocapturing mitochondrial complexes with our
new capture antibodies. 

Each workshop will be limited to 5 participants. The cost
of the course is $2500 for the full 5-day program. We provide
materials but the fee does not cover travel or accommodation. 
However, $1750 of the fee is returned as a credit for purchase
of our antibodies. 

If you, or one of your colleagues, is interested in participating
in one of our workshops, please contact
sales@mitosciences.com for more details and dates.



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