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Volume 02, Number 03 - October, 2006

Mitochondrial Research Bulletin

Published by:
Advancing Vital Discoveries in Mitochondrial Research

Edited by:
Dr. Roderick Capaldi

Volume 02, Number 03 - October, 2006

In this Issue:

Friedreich's Ataxia, New Ideas and Old Controversies


Friedreich's ataxia (FRDA) is the most common inherited ataxia with
an estimated prevalence of 1 in 50,000. It is autosomal recessive
with a carrier frequency of 1 in 120 in the European population.

The disease is characterized by progressive gait and limb ataxia due
to spinal cord dysfunction. Hypertrophic cardiomyopathy is found in
almost all patients and 30% have diabetes and/or metabolic syndrome.
The mutated gene in Friedreich's ataxia is on chromosome 9 and
encodes frataxin, a mitochondrial protein that is approximately 17kD
in size in its monomeric form. The codon GAA is repeated 100-1700
times in both copies of this gene in the majority of patients having
Friedreichs ataxia (FRDA).

FRDA patients show low expression of frataxin with the severity
including progression of symptoms proportionate to the number of
the triplet repeats. Frataxin has been implicated in mitochondrial
iron homeostasis. Rarely, mutations in other proteins, almost all of
which are involved in iron homeostasis, present with the symptoms
of Friedrich's ataxia. However, the vast majority of patients have
altered frataxin levels.

The most often proposed role for frataxin is in the intramitochondrial
synthesis of FeS clusters. Other postulated roles of this protein
include iron transport, iron storage, as a stimulator of oxidative
phosphorylation, and an anti-oxidant function. When reviewing the
literature it is remarkable how little agreement there is, not just on
what the protein does, but on how cells are altered when the protein
is reduced in amount.

The emerging consensus was that accumulation of iron occurs in
Friedreich's ataxia, particularly in the heart, e.g. based on post-mortem
studies such as by Waldvogel D., van Gelldersen.P & Hallett.M.
Ann. Neurol. 46. 123-5 (1999). and that this free iron causes oxidative
damage through free radical generation. (Puccio.H. & Koenig.M. Curr.
Opin.Genet.Dev.12. 272-77. (2002). However more recent studies
with patient cell lines do not show increased free iron e.g. Sturm B.
et. al. J.Biol.Chem. 280. 6701-5 (2005).

In a recent paper " Friedrich's ataxia: the oxidative stress paradox"
Sevnec H. et. al Human Mol. Genetics 14. 463-74 (2005) argue
that oxidative stress may not be an integral part of the disease
progression. These authors tested the effect of increased antioxidant
defenses using a Mn superoxide reductase (SOD) mimetic (MnTBAP)
as well as CuZnSOD over expression to evaluate oxidative damage
in FRDA cardiomyopathy. Based on their studies, they conclude that
mitochondrial iron accumulation does not induce oxidative stress and
propose that FRDA is not associated with oxidative damage.

The evidence that frataxin binds iron is strong as first shown by
Cavadini et al Hum.Mol.Genet. 33.217-27 (2002). and the way it
does so may be the key to multiple different functions of the protein.
Thus as a monomer, or small polymer, frataxin can serve as FeII
donor to non-heme iron forming proteins. However with excess
iron, frataxin forms large assemblies in which the free iron becomes
entrapped. Thus an alternative role for frataxin is as an iron store.
Recently, O.Neill et al Biochemistry 44. 537-45 (2005) provided
support for this latter role and showed that the frataxin/iron assembly
has ferroxidase activity and detoxifies active iron by sequestering
it into this protein-protected compartment. In this respect frataxin
has a more direct anti-oxidant role. In a recent elegant paper,
Gakh et al. have described mutations in yeast frataxin that specifically
impair the ferroxidation or mineralization of frataxin but do not affect
the chaperone function of iron insertion into iron containing centers.
The mutations selectively altering iron binding increase oxidative
stress so that it is the storage rather than failure to make non-heme
iron centers that is physiologically critical.

What other factors affect the phenotype caused by reduced levels
of frataxin. Several gene array studies show that several metabolic
pathways are altered in animals and cells with FRDA. Schonfeld et
al Hum.Mol.Genetics 14.3787-99 (2005) showed that reduced
synthesis of frataxin was associated with reduced levels of transcripts
associated with heme synthesis including enzymes associated with
heme a. They suggest that that the heme defect seen in FRDA is
primary to the pathiophysiological process.

Anther recent paper casts a very different view of the pathology of
FRDA. Irazusta et al J.Biol.Chem (published on line Mar 1 2006)
These authors argue that manganese deficiency is involved.
They show that the activities of aconitase, glutaminate synthase,
succinate dehydrogenase and isopropyl malate dehydratase, 4
non heme iron containing enzymes with reduced activity in FRDA,
are all improved by manganese supplementation. They argue that
the generalized deficiency of iron sulfur proteins could be a
consequence of manganese superoxide dismutase deficiency,
and suggest that Mn supplementation is a therapeutic option.

Not withstanding the controversies fueled by the above recent work,
much effort with regard to therapy for the disease is based on the
idea of accumulated oxidative damage leading to the disease phenotype.
There are now several trials using anti-oxidant therapy including the
use of coenzyme Q and idebenone, two lipid soluble anti-oxidants.
Others are beginning to evaluate gene therapy and altering the
efficiency of transcription of the defective frataxin gene as ways to
increase the levels of frataxin in cells of patients.

** Product Announcement **

Progress in studies of the debilitating disease, and hopes of curing
FRDA, require new technologies to monitor the disease's causes and
effects. MitoSciences has been offering a highly specific monoclonal
antibody to frataxin for immunohistochemical and Western blotting
studies. Now a novel, simple, fast and cheap way has been
developed for following frataxin levels in small amounts of cell extracts
using a lateral flow device (dipstick).

For more information please visit:

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