cron-web.org

[A1CR]

It seems that a new enzyme has been found to be involved in
CR-associated
changes in
http://en.wikipedia.org/wiki/Reactive_oxygen_species and
http://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide
, which is
also in the sirtuin pathway, may be involved. Dihydrolipoyl
dehydrogenase
is a disease that is essential for humans (1).
Dihydrolipoyl dehydrogenase
seems to regulate reactive oxygen species and may be
inhibited by CR and
involved in Saccharomyces cerevisiae lifespand, it seems
(2). In (2),
mutants live 2/3rds as long as wild type yeast; wild type
lived 24% longer
on DCR (0.5% versus 2.0% glucose); mutant lifespan was 55%
longer with CR;
and CRed mutant live 94% as long as wild type yeast with CR.

1. Sakaguchi Y, Yoshino M, Aramaki S, Yoshida I, Yamashita
F, Kuhara T,
Matsumoto I, Hayashi T.
Dihydrolipoyl dehydrogenase deficiency: a therapeutic trial
with
branched-chain amino acid restriction.
Eur J Pediatr. 1986 Sep;145(4):271-4.
PMID: 3769994

A patient with a deficiency of dihydrolipoyl dehydrogenase
and neurological
disease is described. The patient was placed on a
branched-chain amino
acid-restricted regimen. After the introduction of the
regimen, there were
some biochemical improvements and he achieved some
developmental milestones,
in contrast to previously reported patients whose
neurological disease was
progressive. Restriction of the branched-chain amino acids
is worth trying
among therapeutic measures for this disease, although
restriction of the
amino acids alone may not totally prevent progression of
neurological
disease.

2. Tahara EB, Barros MH, Oliveira GA, Netto LE, Kowaltowski AJ.
Dihydrolipoyl dehydrogenase as a source of reactive oxygen
species inhibited
by caloric restriction and involved in Saccharomyces
cerevisiae aging.
FASEB J. 2006 Nov 16; [Epub ahead of print]
PMID: 17110466

Replicative life span in Saccharomyces cerevisiae is
increased by glucose
(Glc) limitation [calorie restriction (CR)] and by augmented
NAD(+).
Increased survival promoted by CR was attributed previously
to the
NAD(+)-dependent histone deacetylase activity of sirtuin
family protein
Sir2p but not to changes in redox state. Here we show that
strains defective
in NAD(+) synthesis and salvage pathways (pnc1Delta,
npt1Delta, and
bna6Delta) exhibit decreased oxygen consumption and
increased mitochondrial
H2O2 release, reversed over time by CR. These null mutant
strains also
present decreased chronological longevity in a manner
rescued by CR.
Furthermore, we observed that changes in mitochondrial H2O2
release alter
cellular redox state, as attested by measurements of total,
oxidized, and
reduced glutathione. Surprisingly, our results indicate that
matrix-soluble
dihydrolipoyl-dehydrogenases are an important source of
CR-preventable
mitochondrial reactive oxygen species (ROS). Indeed,
deletion of the LPD1
gene prevented oxidative stress in npt1Delta and bna6Delta
mutants.
Furthermore, pyruvate and alpha-ketoglutarate, substrates
for dihydrolipoyl
dehydrogenase-containing enzymes, promoted pronounced
reactive oxygen
release in permeabilized wild-type mitochondria. Altogether,
these results
substantiate the concept that mitochondrial ROS can be
limited by caloric
restriction and play an important role in S. cerevisiae
senescence.
Furthermore, these findings uncover dihydrolipoyl
dehydrogenase as an
important and novel source of ROS leading to life span
limitation.--Tahara,
E. B., Barros, M. H., Oliveira, G. A., Netto, L. E. S.,
Kowaltowski, A. J.
Dihydrolipoyl dehydrogenase as a source of reactive oxygen
species inhibited
by caloric restriction and involved in Saccharomyces
cerevisiae aging.

... We found that CR enhances O2 consumption and
concomitantly prevents mitochondrial ROS formation
and glutathione oxidation. Indeed, a strong inverse
correlation between respiratory rates and ROS release
was observed. We also found that decreased NAD
synthesis inhibits respiration, enhances mitochondrial
ROS release, and decreases chronological life span.
Surprisingly, our results suggest that the main CRsensitive
ROS source was not the electron transport
chain but matrix dihydrolipoyl dehydrogenases. This
finding implicates a new mitochondrial ROS source in
cellular life span limitation.