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MitoNews
Mitochondrial Research Bulletin
Published by:
MitoSciences
Advancing Vital Discoveries in Mitochondrial Research
http://www.mitosciences.com
Written by:
Dr. Roderick Capaldi
[email protected]
Volume 01, Issue 09 - September 29, 2005
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Past Issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html
In this Issue:
1. MITOCHONDRIAL ALDEHYDE DEHYDROGENASE
ACTIVATES NITROGLYCERIN AND GENERATES NITRIC
OXIDE
2. VISUALIZING mRNA IN MITOCHONDRIA OF LIVING CELLS
WITH MOLECULAR BEACONS
3. MORE EVIDENCE DOR THE ROLE OF PHOSPHORYLATION
/DEPHOSPHORYLATION IN CONTROL OF MITOCHONDRIAL
FUNCTION: IDENTIFICATION OF A NOVEL PHOSPHATASE
IN MITOCHONDRIA AND ROLE IN INSULIN SECRETION
4. DJ1 IN PARKINSONS DISEASE; ANOTHER
MITOCHONDRIAL LINK
5. CHARCOT-MARIE-TOOTH DISEASE; A MITOCHONDRIAL
DISEASE?
6. MITOCHONDRIAL INVOLVEMENT IN SCHIZOPHRENIA
7-9. INVOLVEMENT OF MITOCHONDRIA IN VIRAL INFECTION
AND INNATE IMMUNITY
10. THE CHEMISTRY OF WHY ACONITASE INACTIVATION
CAN BE USED AS A MEASURE OF THE LEVELS OF OXIDATIVE
STRESS IN CELLS
11. MORE ON THE POLYMORPHISMS OF MITOCHONDRIALLY
ENCODED COMPLEX I GENES AND DISEASE; ABREAST
CANCER CONNECTION?
12. CYTOCHROME C OXIDASE IS A CALCIUM BINDING
PROTEIN
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1. MITOCHONDRIAL ALDEHYDE DEHYDROGENASE
ACTIVATES NITROGLYCERIN AND GENERATES NITRIC
OXIDE
Nitroglycerin (glyceryl trinitrate, GTN) elicits nitric oxide (NO)
signaling to dilate blood vessels and increase oxygenation of
heart tissue. In the study below, Stamler and colleagues add
to the evidence that GTN is bioactivated by mitochondrial
aldehyde dehydrogenase. They show that this bioactivation is
eliminated when mt aldehyde dehydrogenase is genetically
deleted in mice. Generation of vasodilation by other compounds
is not altered in these ALDH minus mice. Thus it appears that
mitochondria can generate NO independently of NO synthase
activity.
CHEN.Z, FOSTER.MW, ZHANG.J, MAO.L, ROCKMAN.HA,
KAWAMOTO.T, KITAGAWA.K, NAKAYAMA.KI, HESS.DT &
STAMLER. JS.
Proc Acad Sci USA 102. 12159-64 (2005)
2. VISUALIZING mRNA IN MITOCHONDRIA OF LIVING CELLS
WITH MOLECULAR BEACONS
Optical techniques for identifying molecules in cells continue to
advance rapidly. In the article below the authors describe
visualization of mRNA for glyceraldehyde 3-phosphate
dehydrogenase in the mitochondria of live cells using molecular
beacons. These reagents are dual labeled antisense
oligonucleotides with a fluorophore at one end and a quencher
at the other. They form stem loop structures in the absence of
a complimentary target, which results in quenching of the
fluorescence. However, on hybridization the structure opens up
and the quenching is lost. The probe is directed to mitochondria
in the study here by using a peptide targeting sequence attached
to the oligonucleotide. The method should have widespread
application in mitochondrial studies.
SANTANGELA.PJ, NITIN.N & BAO.G
J. Biomed. Opt 10. 44025-35 (2005)
3. MORE EVIDENCE FOR THE ROLE OF PHOSPHORYLATION
/DEPHOSPHORYLATION IN CONTROL OF MITOCHONDRIAL
FUNCTION: IDENTIFICATION OF A NOVEL PHOSPHATASE
IN MITOCHONDRIA AND ROLE IN INSULIN SECRETION
The authors describe a new member of the dual-specific protein
tyrosine phosphatase family, that they call PTPMT1 (protein
tyrosine phosphatase mitochondrial 1) which resides almost
exclusively in the matrix space and anchored to the inner
membrane of mitochondria. Knockdown of PTPMT1
expression in a pancreatic insulinoma cell line was found to
alter the mitochondrial phosphoprotein profile and greatly
increase both ATP production and insulin secretion.
PAGLIARINI.DJ, WILEY.SE, KIMBLE.ME, DIXON.JR, KELLY.P,
WORBY.CA, CASEY.PJ & DIXON.JE
Mol.Cell 22. 197-207 (2005).
4. DJ1 IN PARKINSONS DISEASE; ANOTHER
MITOCHONDRIAL LINK
There are now several proteins in which mutations cause
familial early onset Parkinsons disease (PD) including synuclein,
parkin, pink 1 and now DJ1. Pink 1 has been identified as a
mitochondrial protein kinase. The role of DJ1 in cells remains
unknown. However, the study below provides strong evidence
that this is a mitochondrial protein. Thus antibodies to the
protein stained mitochondria in both mouse brain tissues and
human neuroblastoma cell lines. Cell fractionation as well as
immunoelectron microscopy further localized the protein to the
matrix and or inner membrane of the organelle.
ZHANG.L, SHIMOJI.M, THOMAS.B, MOORE.DJ, YU.SW,
MARUPUDI.NI, TORP.R, TORGNER.IA, OTTERSEN.OP,
DAWSON.TM & DAWSON.VL
Hum. Mol. Genet.14. 2063-73 (2005)
5. CHARCOT-MARIE-TOOTH DISEASE; A MITOCHONDRIAL
DISEASE?
Hereditary neuropathies of the Charcot-Marie-Tooth type are
one of the most common inherited neurological diseases.
Several different genes have been identified as causative for
these conditions, including proteins involved in mitochondrial
morphology. In the article below the protein GDAP 1
(ganglioside-induced differentiation-associated protein 1) which
causes a severe autosomal recessive form of neuropathy is
shown by antibody detection of cell fractions to be a
mitochondrial protein of as yet unknown function.
PEDROLA.L, ESPERT.A, WU.X, CLARAMUNT.R, SHY.ME &
PALAU.F
Hum. Mol. Genet. 14. 1087-94 (2005)
6. MITOCHONDRIAL INVOLVEMENT IN SCHIZOPHRENIA
Gene expression pattern changes using cDNA microarrays of
hippocampal dentate granule cells are shown in this study to
be different in schizophrenia patients (22 subjects) and controls
(23 cases). In the schizophrenia patients there is a consistant
decrease in genes for many of the oxidative phosphorylation
enzymes. The same changes were not seen in bipolar patients
(9 cases) or in major depression (10 cases). Other significant
gene alterations were identified in proteasome and cytoskeletal
proteins.
ALTAR.CA, JURATA.LW, CHARLES.V, LEMIRE.A, LIU.P,
BUKHMAN.Y, YOUNG.TA, BULLARD.J, YOKOE.H, WEBSTER.MJ,
KNABLE.MB & BROCKMAN.JA.
Biol. Psychiatry 58. 85-96 (2005).
7-9. INVOLVEMENT OF MITOCHONDRIA IN VIRAL INFECTION
AND INNATE IMMUNITY
Regular readers of this monthly newsletter will have seen several
articles identifying viral proteins that are targeted to mitochondria,
implying involvement of this organelle in viral infections and/or
responses.
The first of three recent articles referenced below provides a
useful review of the information to date. The authors provide
a list of viruses encoding mitochondrially targeted proteins which
includes Epstein-Barr virus, Karposi's sarcoma herpes virus,
hepatitis B and C, papillomavirus and others. Many of the proteins
produced are bcl2 homologues and affect apoptosis.
The second paper, a recently appearing article in Cell, identifies
a novel protein involved in one of the pathways by which cells
sense the presence of infectious microorganisms and develop
an antimicrobial defence. The authors call this protein MAVS
and show that it works on a pathway involving the RNA helicase
RIG1 which promotes expression of IFNbeta. Further, the
authors show that MAVS is localized to mitochondria.
The third paper by McWhirter et al provides a useful perspective
on the exciting implication that mitochondria are involved in innate
immunity.
D'AGOSTINO.MD, BERNARDI.P, CHIECO-BIANCHI.L & CIMINALE.V.
Adv Cancer Res. 94. 87-142 (2005)
SETH.RB, SUN.L, EA.CK & CHEN ZJ.
Cell.122. 669-682 (2005)
McWHIRTER.SM, TENOEVER.BR. & MANIATIS.T.
Cell.122. 645-7 (2005)
10. THE CHEMISTRY OF WHY ACONITASE INACTIVATION
CAN BE USED AS A MEASURE OF THE LEVELS OF OXIDATIVE
STRESS IN CELLS
Aconitase is an important component of the Krebs cycle.
Measurement of activity of the enzyme is rarely done to
evaluate throughput of substrates in this important energy
metabolism step, but rather is used to measure the levels of
oxidative stress in cells. In the article below the details of how
oxidative damage and particularly peroxynitrite reaction inhibits
the enzyme have been worked out. It is shown that peroxynitrite
nitrates with 2 tyr residues (151 and 472) and oxidizes 2 cys
residues (126 and 385) to sulfonic acids. Residue cys 385 is one
of three cys residues that bind the active site Fe-S cluster Other
modifications of the active site cys including S-glutathionylation
also decrease enzymatic activity.
HAN.D, CANALI.R, GARCIA.J, AGUILERA.R, GALLAHER.TK &
CADENAS.E
Biochemistry 44. 11986-96 (2005)
11. MORE ON THE POLYMORPHISMS OF MITOCHONDRIALLY
ENCODED COMPLEX I GENES AND DISEASE; ABREAST
CANCER CONNECTION?
The 10398A allele in mtDNA received notoriety a few years
ago with the finding that this polymorphism is linked to Parkinsons
disease. In the paper below, the authors find a linkage to invasive
breast cancer in African-American women This group harbor the
polymorphism less frequently than Caucasians. A study of 654
cases of African Americans and 605 controls found that the10398
allele is an independent risk factor with no similar association in
Caucasians.
CANTOR.JA, KALLIANPUR.AR, PARL.FF & MILLIKAN.RC.
Cancer Res. 65. 8028-33 (2005).
12. CYTOCHROME C OXIDASE IS A CALCIUM BINDING
PROTEIN
In more innocent times, and before we new much about the
structure of OXPHOS proteins, Racker and colleagues
described the calcium transporting properties of cytochrome c
oxidase. Now nearly 40 years later a Ca++ binding site for the
cation has been located. It is near heme a and involves Asp 477
in the bacterial enzyme. In mammals the same site exists which
can bind one Ca++ or 2 Na+ sites. The Na+ sites have been
modeled in the structure of the bovine enzyme and are 7.4
angstoms apart.
KIRICHENKO.AV, PFITZNER.U, LUDWIG.B, SOARES.CM,
VYGODINA.TV & KONSTANTINOV.AA.
Biochemistry 44. 12391-401 (2005)
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