Brown, Guy C.

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S58 ABSTRACTS / Biochimica et Biophysica Acta 1777 (2008) S2–S111However, under a range of pathological conditions NO levels can rise to
micromolar levels and disrupt a wide range of cellular processes.
Between these two extreme concentration ranges NO can interact with
mitochondria in ways that have been described as physiological or
pathophysiological. The highest afﬁnity target is cytochrome c oxidase.
This talkwill review this interaction and suggest that it has the potential
to play a role in both NO signalling and detoxiﬁcation. NO has also been
shown to interact with lower afﬁnity with mitochondrial cytochrome c
in both its reduced and oxidised forms. Previous studies have indicated
that NO can oxidise cytochrome c at physiological pH. We show that
most of this oxidation is not caused by direct reactions of NO, but
instead by a reaction product of NO and oxygen, most likely NO2. In
contrast the reaction of NO with oxidised cytochrome c is a direct,
reversible binding. Intriguingly in the presence of cardiolipin NO can
also bind reduced cytochrome cwithhigh afﬁnity at neutral pH.Wewill
describe these interactions and comment on their biological relevance.
doi:10.1016/j.bbabio.2008.05.227
S10/2 Mitochondria and reversible apoptosis
Guy C. Brown
Department of Biochemistry, University of Cambridge, UK
E-mail: gcb@mole.bio.cam.ac.uk
Apoptosis has been considered as a form of cell death, to which a
cell is irreversibly committed once cytochrome c is released from the
mitochondria. However, apoptosis can also be regarded as a means of
signalling to phagocytes, which may in principle be reversible up to
the point of phagocytosis. We ﬁnd that mitochondrial cytochrome c
release does not inevitably commit a cell to death because if the cell
reduces the cytosolic cytochrome c then caspase activation is blocked.
Similarly caspase activation does not inevitably commit a cell to death,
because the caspases can be inactivated by endogenous oxidants.
Phosphatidylserine ﬂip to the outer leaﬂet of the plasma membrane is
also a reversible process, as long as phagocytes are not present to eat
the cell. We ﬁnd that many aspects of apoptosis are fully reversible in
neurons. This leads to the conclusion that apoptosis can (in some
circumstances) be reversible and is not always a form of cell death.
doi:10.1016/j.bbabio.2008.05.228
S10/3 Ischemic preconditioning invokes multiple mechanisms of
nitric oxide and reactive oxygen signaling at the mitochondrial
level
Paul S. Brookes
Department of Anesthesiology, University of Rochester Medical Center,
Rochester, NY, USA
E-mail: paul_brookes@urmc.rochester.edu
Ischemic preconditioning (IPC) is a phenomenon in which short
cycles of ischemia and reperfusion (IR) can protect organs such as the
heart and brain from prolonged IR injury. Mounting evidence suggests
that both mitochondria and nitric oxide play critical roles in IPC
signaling, although the exact biochemical mechanisms underlying
cardioprotection are poorly understood. We have identiﬁed 3 novel
biochemical events involving reactive oxygen and nitrogen species,
which may contribute to the modulation of mitochondrial function in
IPC: (1) S-nitrosation and reversible inhibition of respiratory chain
complex I. (2) Activation of mild uncoupling via the generation of NO
derived electrophilic lipids (nitro-alkenes) and their post-transla-
tional modiﬁcation of mitochondrial carrier family proteins. (3)
Endogenous generation of mitochondrial K+ATP channel agonists andcomplex II inhibitors, via redox reactions involving Krebs' cycle
intermediates. Together, it is thought that these 3 pathways all act to
diminish mitochondrial Ca2+ overload and ROS generation at reperfu-
sion, thereby limiting the opening of the permeability transition pore.
A brief outline of the key ﬁndings in support of these novel signaling
pathways will be discussed.
doi:10.1016/j.bbabio.2008.05.229
(S10) Mitochondria and reactive oxygen containing species
symposium abstracts (poster and raised abstracts)
S10.4 Mild uncoupling reduces oxidative stress in intact cells
Alexander M. Wolf, Sadamitsu Asoh, Ikuroh Ohsawa, Shigeo Ohta
Department of Biochemistry and Cell Biology, Institute of Development
and Aging Sciences, Graduate School of Medicine, Nippon Medical
School, Japan
E-mail: awolf@nms.ac.jp
“Mild uncoupling”, the introduction of a limited proton conduc-
tance into themitochondrial innermembrane, has been demonstrated
to greatly reduce reactive oxygen species (ROS) production in isolated
mitochondria. On the other hand, it will also increase energy
consumption to maintain the mitochondrial membrane potential,
and cells need energy in the form of NADH to maintain the cellular
protein machinery in the normal, reduced state. For this reason it has
been a subject to debate whether mild uncoupling is a viable strategy
to reduce oxidative stress in intact cells and ultimately in vivo, or
whether the increased energy expenditure might have detrimental
effects. Using a redox-sensitive green ﬂuorescent protein (roGFP1)
targeted to mitochondria of PC12 cells, we found that mild uncoupling
using low concentrations of chemical uncouplers FCCP or DNP indeed
reduced oxidative stress, whereas strong uncoupling caused oxidation
of roGFP1, indicating that the beneﬁcial effects of uncoupling are
limited to a certain range of membrane potential, and that uncoupling
beyond this range will increase oxidative stress probably due to
energy crisis. This leads to the conclusion that while mild uncoupling
might be beneﬁcial under some circumstances, it is a dangerous
strategy since the safe range of uncoupling will probably depend on
cell type and metabolic state.
doi:10.1016/j.bbabio.2008.05.230
S10.5 The role of reactive oxygen and nitrogen species in the
pathogenesis of acute renal failure
Egor Plotnikova, Anastasia Chupyrkinaa, Alena Vasilevaa,
Aleksandr Kazachenkob, Vladimir Kirpatovskyb, Dmitry Zorova
aA.N. Belozersky Institute, Moscow State University, Moscow, Russia
bResearch Institute of Urology, Moscow, Russia
E-mail: plotnikov@genebee.msu.ru
The aim of this work was to study mechanisms of acute renal
failure (ARF) development in kidney survived ischemia or mioglobi-
nuria (rabdomyolysis). Experimental model of those pathologies
showed that 3 days after ischemia or induction of rabdomyolysis,
the levels of urea, creatinine and cell death markers increase. Such
kidney malfunctioning can be caused by tubular epithelium destruc-
tion. In our experiments, lipid peroxidation products accumulated in
kidney and total antioxidant activity of blood are decreased. Also the
level of nitrite in blood serum was increased indicating the activation
of NO production. Analysis of ROS- and NO-production in kidney cells
revealed ampliﬁcation of the production of these radicals. We


S10/2 Mitochondria and reversible apoptosis 

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S10/2 Mitochondria and reversible apoptosis

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