Resources > MitoNews > Archives > Volume 03, Number 03 - October, 2007

Volume 03, Number 03 - October, 2007




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MitoNews
Mitochondrial Research Bulletin

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

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

Volume 03, Number 03 - October, 2007
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Past Issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html


CONTROL OF CYTOCHROME C OXIDASE LEVELS IN CELLS;
ITS IN THE GENES AND IN A SET OF KINASES.


In this Issue:

1. COX and HIF.

2. Phosphorylation: who, when and why?

3. Takeover of COX in Alzheimer’s disease.
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An area of increasing interest is the regulation of mitochondrial
control. The transcriptional control of the biogenesis of
mitochondria, and the retrograde signaling between the
mitochondrion and the nucleus, are now beginning to be
understood and even exploited in new drug development. Control
of mitochondrial functioning, and regulation of oxidative
phosphorylation in particular has, to date, largely taken a back seat
but this is changing. Essential reading for anyone interested in this
regulation at the enzyme level is a review describing the extent to
which kinases and phosphatases are involved in control of
mitochondrial functioning.

PAGLIARINI & DIXON TRENDS IN BIOCHEM. SCI. 31. 26-34 (2006).

Here I focus more specifically on some old but mainly recent work
on the control of cytochrome c oxidase (Complex IV). The
emerging picture is one in which this enzyme “can” be controlled
by multiple mechanisms. The challenge now is to work out which
processes are in play in different tissues and the signals that
produce the up and down regulation of the enzyme activity.

To understand new developments it helps to know a little history.
For many years Bernard Kadenbach and colleagues waged a lonely battle
to convince the cytochrome c oxidase aficionados that the enzyme was
regulated in tissue specific manner through isoforms of key subunits
and through binding of nucleotides
e.g. NAPIWOTSKI & KADENBACH BIOL CHEM 379. 335-9 (1998).

The momentum to consider why and how COX regulation occurred
was accelerated by the observation by Poyton and associates for
yeast, ALLEN et al.J.BIOL.CHEM. 270.110-18 (1995) and then Bisson
and colleagues for Dictyostelium, BISSON et al. EMBO J. 16.
739-49 (1997) that there was an oxygen-dependent switch
of subunit isoforms. This involved switching of subunit V of yeast, which
is the homologue of the mammalian subunit IV, and subunit VII in Dictyostelium,
the mammalian subunit VIII equivalent.

Since the pioneering work above, additional isoforms of several
subunits of COX in mammals have been described
(HUTTEMANN et. al. MOL. REPROD. DEV. 66.8-16 (2003),
including 2 forms of subunit IV (HUTTEMANN et. al. GENE 267.
111-23 (2001), but the functional significance of these had not
been clear. Also the interaction between nucleotides and COX has
been extended to include binding at ATP and ADP specific sites,
and more recently, by phosphorylation via kinases. In additional a
beginning has been made in identifying the signaling pathways that
lead to changes in COX levels, isoform composition and turnover.

1. COX and HIF
-------------------------

A link between COX activity and oxygen tension in mammals
seemed likely given the yeast data but identification of the factors
involved has been elusive until recently. However 3 papers now
link translational control of the two isoforms of COX IV to
hypoxia via HIF regulation. In a study by HERVOUT ET AL.
BIOCHEM. BIOPHYS. RES COMMUN. 344. 1086-1093 (2006)
the authors used human cell lines treated with the hypoxia mimic
cobalt chloride to induce HIF and showed that this resulted in loss
of the normal processing of the COXIV precursor, but they do not
indicate which isoform is involved.

FUKADA et al CELL 129. 111-122 (2007) provides a more
extensive description of the effect of HIF, showing that hypoxic
conditions switch COX IV isoforms by activating transcription of
COX subunit IV-2 as well as LON, a protease that degrades COX
IV-1. These authors use human and mouse cell lines for their
experiments. Finally, HUTTERMANN et al. FEBS JOURNAL
274. 5737-48 (2007) reported that COX-IV-2 is up-regulated in
hypoxia via a novel conserved oxygen responsive element. They
report that COX IV-2 is transcribed in lung, trachea, a small
amount in aorta and small intestine muscle, but not in skeletal
muscle.

2. Phosphorylation: who, when and why?
----------------------------------------------------

There have been a number of reports of phosphorylation of COX
subunits as follows:

STEENAART & SHORE FEBS LETT. 415. 294-98 (1997)
showed that subunit IV of mammals is phosphorylated. At this
time the existence of isoforms of this subunit was not well
documented. More recently, FANG et. al. FEBS LETT 581. 1302-
10 (2007) report that phosphorylation of subunits I, IV -1 and Vb
is induced by ischemia/reperfusion in heart. Very recently it has
been reported that protein kinase C-epsilon co-immunoprecipitates
with COX IV and so this may be the kinase responsible for this
modification.

GUO et al. AM.J. PHYSIOL.HEART.CIRC.PHYSIOL 293.H2219-30 (2007).

Phosphorylation of subunit I has been reported By LEE et. al. J.
BIOL.CHEM, 280. 6094 (2005) through a cyclic AMP dependent
pathway. A phosphorylation of subunit II mediated by binding of
the epidermal growth factor receptor has been reported.

(BOERNER et al. MOL &CELL BIOL. 24. 7059-71 (2004).

Also AUGUREAU et. al CMLS CELL MOL.LIFE SCI 62. 1478-88 (2005)
reports a tyrosine phosphorylation of subunit II using a
whole mitochondria-scanning approach.

Proteomic approaches have identified yeast COX IV (mammalian
Vb and COX VIa (also VIa in mammals) as phosphorylated
proteins. REINDERS et al. MOL.CELL PROTEOMICS
PUBLISHED ONLINE AUG 29. (2007), while HOPPER et al.
BIOCHEMISTRY 45. 2524-36 (2006) reports that VIa is
phosphorylated in beef heart. Thus in total, we are looking at
phosphorylation of I, II, IV, Vb, and VIa under various conditions.

In summary, complex IV is clearly controlled in response to
cellular metabolic changes in short term by phosphorylation/de-
phosphorylation events and in longer term by isoform switching,
and these same changes may prime the enzyme for the different
energetic needs of different tissues but all this remains to be fully
explored. Presumably at least a part of the complexity is related to
the need to maximize and efficiently utilize oxygen under all
cellular conditions in order to minimize the levels available to react
with flavins and non-heme iron centers to generate pathological
free radicals.

BUT WAIT THERE’S MORE:

3. Takeover of COX in Alzheimer’s Disease
----------------------------------------------------

Above is a summary of control of cytochrome c oxidase as a part
of metabolic homeostasis. What if this gets high-jacked!!!!

Two recent reports link the pathology of Alzheimer’s diseases to
such a high-jacking. It has been reported by several groups that
cytochrome c oxidase activity is reduced in the brains of AD
patients, but how? Trounce and colleagues CROUCH et. al. J. of
NEUROCHEM. 99. 226-36 (2006) recently described that the 42
amino acid Abeta peptide specifically inhibited COX activity.
More recently HONG et. al. NEUROCHEM. RES. 32. 1483-88
(2007) reported that this AD associated peptide affected COX
subunit expression!

FOR MORE INFORMATION ON CYTOCHROME C OXIDASE
THE READER IS REFERRED TO OUR RECENTLY
PUBLISHED CYTOCHROME C OXIDASE PLAYBOOK,
AVAILABLE FOR FREE DOWNLOAD FROM THE
MITOSCIENCES WEBSITE.

http://mitosciences.com/PDF/MitoSciences_Complex_IV_Playbook.pdf



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