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Volume 01, Issue 01 - January, 2005




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MitoNews: Research Bulletin & Discussion Forum

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

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

Issue 1 - January 19, 2005
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Contents:

RECENT RESEARCH
1. NO regulates mitochondrial biogenesis
2. Elongation factor G1 causes hepatoencephalopathy
3. Charcot-Marie-Tooth neuropathy caused by mutation
of mitochondrial mitofusin 2
4. Cocaine and control of mtDNA levels
5. Mitochondrially generated oxidative stress, lifespan and
neurodegeneration
6. Drugs for obesity remodel mitochondria
7. The ATP synthase inhibitor protein IF1 modulates
angiogenesis
8. SCO2 and cytochrome c oxidase deficiency
9. Ligands of the peripheral benzodiazipine receptor in
mitochondria induce apoptosis and cell cycle arrest.
10. Aspirin and inhibition of cardiac mitochondrial
functioning
11. Mitochondrial protein alterations in heart with aging
show gender specificity
12. OPA1 and mitofusin 1 work together to promote
mitochondrial fusion.
13. MtDNA polymerase gamma mutatons and the risks
of early menapause and Parkinsonism
14. Relationship between genotype and phenotype in
mitochondrial disease
15. Mitochondria and cancer; new mitochondrial
proteins: unknown function


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

1. NO regulates mitochondrial biogenesis

NO is an important signaling molecule which according to
the recent research below regulates mitochondrial biogenesis
in mammalian cells and tissues. Long term exposure of cells
in culture to NO increased cell respiration and ATP production
while glycolysis was unchanged. Tissues from mice null for
the endothelial NO synthase had reduced ATP production,
lower mitochondrial content and altered mitochondrial
morphology.

NISOLI.E, FALCONE.S, TONELLO.C, COZZI.V, PALOMBA.L,
FIORANI.M, PISCONTI.A, BRUNELLI.S, CARDILE.A,
FRANCOLINI.M, CANTONI.O, CARRUBA.MO, MONCADA.S &
CLEMENTI.E. 
Proc. Natl. Acad. Sci. USA 101. 16507-12 (2004)



2. Elongation factor G1 causes hepatoencephalopathy

A severe form of mitochondrial dysfunction in two siblings 
with much reduced levels of mitochondrially encoded
subunits of OXPHOS has been mapped to the elongation
factor 3.

COENEN.MJ, ANTONICKA.H, UGALDE.C, SASARMAN.F,
ROSSI.R, HEISTER.JG, NEWBOLD.RF, TRIJBELS.FJ,
VAN DEN HEUVEL.LP, SHOUBRIDGE.EA & SMEITINK.
JA. N. ENGL. J. MED 351. 2080-6 (2004)



3. Charcot-Marie-Tooth neuropathy caused by mutation
of mitochondrial mitofusin 2

Charcot-Marie-Tooth disease has several forms, one of
which has now been linked to mutations in the mitochondrial
fusion protein mitofusin 2. These findings add to the
growing evidence of the importance of mitochondrial
network formation and disassembly for mitochondrial
functioning particularly in nerve axons

KIJAMA.K, NUMAKURA.C, IZUMINO.H,UMETSU.K,
NEZU.A, SHIIKI.T, OGAWA.M, ISHIZAKI.Y, KITAMURA.T,
SHOZAWA.Y & HAYASAKA.K.
Hum Genet. 116. 23-7 (2005)



4. Cocaine and control of mtDNA levels

A recent differential gene expression display study of
acute cocaine administration shows clear down regulation
of multiple mitochondrially encoded genes in the
cingulated cortex of the brain in rats.

DIETRICH. J.B, POIRIER. R, AUNIS. D & ZWILLER J ANN.
N.Y. ACAD. SCI 1025 345-50 (2004)



5. Mitochondrially generated oxidative stress, lifespan and
neurodegeneration

The authors compare the rates of neurodegeneration
caused by the equivalent mutations in a diverse group of
genes from five mammalian species with different lifespan
potentials. They find that neurodegeneration rates vary
by two orders of magnitude and are strongly correlated
with lifespan from which they conclude that steady-state
reactive oxygen and nitrogen species production is the
principal factor setting the probability of cell death.

WRIGHT.AF, JACOBSON.SG, CIDECIYAN.AV, ROMAN.AJ,
SHU.X, VLACHANTONI.D, MCINNES.RR & RIEMERSMA.RA.
NAT GENET. 36. 1153-8 (2004)



6. Drugs for obesity remodel mitochondria

Drugs that enhance insulin sensitivity appear to exert their
therapeutic affect through adipose tissue. One such drug,
rosiglitazone, has been shown to alter both morphology and
protein profiles of mitochondria in adipocytes in cell culture. 
In the present study the effect of the drug was studied using
white adipocytes from ob/ob mice during development of
obesity and after treatment with rosiglitazone. The levels of
almost half of the gene transcripts for mitochondrial proteins
were found to be decreased with onset of obesity and about
half of these were upregulated after the drug treatment and
there was increased mitochondrial mass.

WILSON-FRITCH.L, NICOLORO.S, CHOUINARD.M,
LAZAR.MA, CHUI.PC, LESZYK.J, STRAUBHAAR.J,
CZECH.MP & CORVERA.S. J.
CLIN. INVEST. 114. 1281-9 (2004)



7. The ATP synthase inhibitor protein IF1 modulates
angiogenesis

The evidence for an ³ectopic² F1F0ATP synthase on the
plasma membrane of cells is strongest for endothelial cells
where it acts as the angiostatin receptor. In mitochondria,
the functioning of the ATP synthase is controlled by an
endogenous inhibitor IF1. In the study below IF1 is shown
to be present on the plasma membrane of endothelial cells. 
Itıs binding to the F1 part inhibits ATP hydrolysis at acid pH
but does not affect ATP synthesis. This is in contrast to
angiostatin, which inhibits both forward and reverse reactions
of the enzyme. IF1 did not inhibit cell differentiation to form
tubes and only slightly inhibited cell proliferation. Angiostatin
blocked IF1 interaction with F1 but not vice versa. The
authors conclude that IF1 serves a protective role for
endothelial cells in the acid tumor environment.

BERWICK.NR, WAHL ML, ZHONG.Z, CAPALDI.RA,
KENAN.DJ & PIZZO.SV. 
J.Biol. Chem. 280. 1740-5 (2005)



8. SCO2 and cytochrome c oxidase deficiency

Cytochrome c oxidase (COX) is a copper containing enzyme.
This copper enters mitochondria and is inserted into the
enzyme complex during assembly. A number of proteins
are involved in this process including SCO2. An increasing
number of mutations in the SCO2 gene are being described
which alter COX assembly, causing fatal cardiomyophathies
and encephalopathies. In the study below the authors
analyse several such mutants by activity measurements of
COX and assembly of this complex by BNPAGE using
antibodies available from MitoSciences.

VESELA.K, HANSIKOVA.H, TESAROVA.M, MARTASEK.P,
ELLEDER.M, HOUTEK.J & ZEMAN.J,
ACTA PAEDIATR 93. 1312-7 (2004)



9. Ligands of the peripheral benzodiazipine receptor in
mitochondria induce apoptosis and cell cycle arrest.

Ligands of the peripheral benzodiazipine receptor (PBR)
are known to inhibit the proliferation of various tumors. 
In the study below, the effect of such ligands was examined
in human hepatocellular carcinoma cells (HHC cells). 
PBR was localized to mitochondria in both in these cell
lines and in tumor tissue from patients with hepatocellular
carcinoma, while normal liver did not express the protein. 
PBR ligands inhibited proliferation of the HHC by inducing
apoptosis characterized by overexpression of Bax and
suppression of Bcl-2. Synergistic anti-neoplastic effects
could be obtained when the PBR ligands were used in
conjunction with doxorubicin, indicating a sensitization
effect which could be important in cancer therapy.

SUTTER.AP, MAASER.K, GRABOWSKI.P, BRADACS.G,
VORMBROCK.K, HOPFNER.M, KRAHN.A, HEINE.B, STEIN.H,
SOMASUNDARAM.R, SCHUPPAN.D, ZEITZ.M &
SCERUBL.H.
J. HEPATOL. 41. 799-807 (2004)



10. Aspirin and inhibition of cardiac mitochondrial functioning

Acetylsalicylate may be the most prescribed drug and has a
good safety record except for rare gastrointestinal bleeding.
In a new study of the effect of the drug on isolated mitochondria
below the authors show that coupled respiration is altered and
that aspirin inhibits alpha ketoglutarate dehydrogenase.

NULTON-PERSSON.AC, SZWEDA.LI & SADEK.HA.
J.CARDIOVASC.PHARMACOL 44. 591-5 (2004)



11. Mitochondrial protein alterations in heart with aging show
gender specificity

Proteomics is finding widespread use in mitochondrial
research. In the recent study below, 2D gel ectrophoresis
and mass spectrometry was used in a comparative study
of the effects of aging on the hearts of male and female
monkeys. Significantly lower levels of enzymes of glycolysis
the TCA cycle and oxidative phosphorylation, as well as
pyruvate dehydrogenase, were seen in hearts from older
males compared with younger males or both young and
old females.

YAN.L, GE.H, LI.H,LIEBER.SC,NATIVIDAD.F,RESUELLO.RR,
KIM.SJ,.AKEJU.S,SUN.A, LOO.K, PEPPAS.AP, ROSSI.F,
LEWANDOWSKI.ED,THOMAS.AP & VATNER.DE.
J. MOL.CELL CARDIOL 37. 921-9 (2004)



12. OPA1 and mitofusin 1 work together to promote
mitochondrial fusion.

OPA 1 is a dynamin related protein of the mitochondrial
inner membrane mutated in autosomal dominant optic
atrophy. It is involved in the formation of the branched
network morphology of mitochondria in mammalian cells. 
In the study below, OPA1 levels were stably reduced by
RNA interference resulting in small, fragmented and
scattered mitochondria. Additonal data showed that OPA1
required the outer membrane protein mitofusin 1 but not
mitofusin 2 to tubulate and fuse mitochondria indicating
for the first time a distinct functional difference between
the two mitofusins.

CIPOLAT.S, DE BRITO.OM, DAL ZILIO.B & SCORRANO.L. 
PROC. NATL. ACAD. SCI. USA. 101. 15927-32 (2004)



13. MtDNA polymerase gamma mutatons and the risks of
early menapause and Parkinsonism

Mutations in mtDNA pol gamma(POLG) are associated with
both autosomal dominant and recessive progressive external
opthalmoplegia. In recent studies in 7 families with this
desease significant cosegregation of Parkinsonism was seen
including PET scan detection of dopaminergic neuron loss.
There was early menapause (before 35 years) and at the
molecular level secondary accumulation of mtDNA mutations
in the patientıs tissue

Luoma P, Melberg.A, Rinne JO, Kaukonen JA, Nupponen NN,
Chalmers RM, Oldfors A, Rautakorpi I, Peltonen L,
Majamaa K, Somer H & Suomalainen A. 
Lancet 364 875-82 (2004)



14. Relationship between genotype and phenotype in
mitochondrial disease

The relatioship between the molecular basis of mitochondrial
disease and the presentation of the patient is extremely
variable. Heteroplasmy of mtDNA mutations , threshold
effects that vary with different tissue and the large number of
different genes involved in this class of diseases are all
contributing factors. In the article below the
phenotype-molecular basis of 113 pediatric patients has
been correlated. Among the interesting findings, 71 of the
group had identifiable defects in one or more of the respiratory
chain complexes. Only 11.5% had pathogenic mtDNA
anomalies. 40% had cardiac disease and 60% neuromuscular
manifestations. The mean age of the group was 40 months
at presentation.

Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO,
Neish SR, Ware SM, Hunter JV, Fernbach SD, Vladutiu GD,
Wong LJ & Vogel H. 
Pediatrics 114 925-31 (2004)



15. Mitochondria and cancer; new mitochondrial proteins:
unknown function

A recent screen for novel genes involved in taxol resistance
has identified one that is consistently overexpressed in taxol
and doxorubicin resistant cell lines by as much as 12 and 6
fold respectively. This is a single copy gene on chromosome
7q21. The gene product MM-TRAG (Mitochondrial Taxol
Resistance Associated Gene protein) was found to be
localized in mitochondria and ubiquitously expressed in
tissues.

Duan Z, Brakora KA, Seiden MV. 
Gene 340 53-9(2004)



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