Resources > MitoNews > Archives > Volume 01, Issue 10 - November, 2005

Volume 01, Issue 10 - November, 2005




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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
rcapaldi@mitosciences.com

Volume 01, Issue 10 - November 30, 2005
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Past Issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html


2005 HAS BEEN A BANNER YEAR IN COMPLEX I RESEARCH

This last year has seen some impressive advances in our
understanding of the structure, functioning and mis-functioning
of mitochondrial Complex I. One piece of particularly good news;
no more subunits have been added to the complex, we are still
at 46! Below are some important papers on this complex to
appear in the last 12 months.


Structural information:
----------------------------
1) A 4angstrom map of the peripheral domain of complex I from
T. thermophilus shows the location of one binuclear and 6
tetranuclear FeS clusters arranged as an essentially linear chain
through the molecule for 84angstroms with each center maximally
14 angstroms apart. The two other centers in the complex N1a
and N7 are not in the pathway.

HINCHLIFFE.P. & SAZANOV.L.A.
Science 309 771-774 (2005).


2) A full proteomic analysis of the post-translational modifications
of the nuclear encoded subunits of complex I from beef heart has
been completed. This study identifies 13 subunits as N-alpha-
acetylated and one N-alpha-myristoylated.

CARROLL.J., FEARNLEY.I.M., SKEHEL. J.M, RUNSWICK. M.J,
SHANNON. R.J, HIRST.J. & WALKER .J.E.
Mol.Cell Proteomics 4. 693-9 (2005).



Assembly information:
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The number of identified assembly factors for complex I has
increased from 0 to 3 this year with at least one big surprise
in terms of the proteins involved.

3,4) Strong evidence had been presented that the pro-apoptotic
protein AIF (apoptosis-inducing factor) is involved in complex I
assembly. Human and mouse cells lacking AIF showed much
reduced oxidative phosphorylation capacity because of severe
reduction of complex I activity and amount. Also Harlequin mice
with reduced AIF expression had reduced OXPHOS and
significantly reduced complex I assembly leading to retinal and
brain defects.

VAHSEN N AND 20 CO-AUTHORS.
EMBO J. 23 4679-89 (2004).


In a more recent paper the unexpected role of AIF was
confirmed and it was shown that protein retaining NADH
oxidase activity was essential for this functioning.

URBANO.A., LAKSHMANAN. U., CHOO. P.H., GUO.K.
DHAKSHINAMOORTHY.S. &. PORTER.A.
EMBO.J. 24. 2815-26 (2005).


5,6) Two other chaperones for complex I assembly were
reported this year. The first is called B917.2L) as it is a
paralogue of the structural subunit B17.2 (17% identical;
31% similar).

OGILVIE. I., KENNAWAY. N.G. & SHOUBRIDGE. E.A.
J. Clinical Invest. 115. 2784-2792 (2005)


The second one is a larger protein, the homologue of a
complex I chaperone in Neurospora crassa (CIA30) called
NDUFAF 1.

VOGEL R.O AND 11 CO-AUTHORS
FEBS J.272. 5317-26 (2005)


Deletion or pathogenic mutations in both assembly factors
reduce or abolish the full complex I assembly but partial
assemblies can be identified. It is proposed that both are
involved in stabilizing intermediates in the assembly pathway.



Complex I pathology, superoxide production, and cell
biological effects:
--------------------------------------------------------------------
7,8,9) Three important papers add insight into what happens
in the cell when complex I dysfunction induces superoxide
formation. One study shows that the superoxide production
occurs through O radical production at the FMN site. The work
further shows that a consequence of the radical formation is
inactivation of the enzyme via oxidative modification of two
sites a cysteine and a tyrosine in the 51Kd subunit.

CHEN. Y-R., CHEN. C-L., ZHANG.L. GREEN-CHURCH.K.B. &
ZWEIER.JL.
J. Biol. Chem.. 280.37339-48 (2005)


Two papers from the Nijmegen groups of Smeitink and Willems
begin to describe the effects of complex I on the properities of
mitochondria in the cell. They describe the correlation between
reduced functioning of complex I, increased oxygen radical
formation and changes in the overall morphology of the
mitochondria.

KOOPMAN et al.
Am. J. Physiol. Cell Physiol 288 C1440-50 2005.

KOOPMAN et al
ibid 289 C881-90 2005



Complex I inhibitors as anti-cancer agents:
------------------------------------------------------
10,11) Potent inhibitors of complex I called acetogenins are
under study as cytotoxic agents against tumor cells. Two
recent studies of these naturally occurring and now
synthetically synthesized compounds have appeared this year.

One is a mechanistic study of the chemical entity for optimal
effect.

ABE.M. et al
Biochemistry 44. 14898-906 (2005)


The second paper shows that the specific structure of the
acetogenin determined the potency of thee compound for
complex I inhibition and that this was correlated with in vitro
anti-tumor potency.

TORMO.JR. et al
Oncol.Res. 15. 129-38 (2005)



Viruses, Complex I and an increase in ROS:
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12) It has been known for some time that hepatitis C infection
causes a chronic state of oxidative stress, which contributes to
the pathology of the virus infection. In the paper below the
authors use transgenic mice expressing HCV core protein to
show that the viral infection reduces complex I activity thereby
increasing ROS production and at the same time causes
oxidation of the glutathione pool.

KORENAGA.M., WANG.T., LI.Y.,SHOWALTER.LA.,CHAN.T,
SUN.J. & WEINMAN.SA.
J.Biol. chem. 280. 37481-8 (2005)



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