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Fatigue & Energy


Role of cysteine and glutathione in HIV infection and other diseases
associated with muscle wasting and immunological dysfunction.
Dr oge W; Holm E
Division of Immunochemistry, Deutsches Krebsforschungszentrum,
Heidelberg, Germany.
FASEB J, 11(13):1077-89 1997 Nov
The combination of abnormally low plasma cystine and glutamine levels,
low natural killer (NK) cell activity, skeletal muscle wasting or
muscle fatigue, and increased rates of urea production defines a
complex of abnormalities that is tentatively called "low CG syndrome."
These symptoms are found in patients with HIV infection, cancer, major
injuries, sepsis, Crohn's disease, ulcerative colitis, chronic fatigue
syndrome, and to some extent in overtrained athletes. The coincidence
of these symptoms in diseases of different etiological origin suggests
a causal relationship. The low NK cell activity in most cases is not
life-threatening, but may be disastrous in HIV infection because it may
compromise the initially stable balance between the immune system and
virus, and trigger disease progression. This hypothesis is supported by
the coincidence observed between the decrease of CD4+ T cells and a
decrease in the plasma cystine level. In addition, recent studies
revealed important clues about the role of cysteine and glutathione in
the development of skeletal muscle wasting. Evidence suggests that 1)
the cystine level is regulated primarily by the normal postabsorptive
skeletal muscle protein catabolism, 2) the cystine level itself is a
physiological regulator of nitrogen balance and body cell mass, 3) the
cyst(e)ine-mediated regulatory circuit is compromised in various
catabolic conditions, including old age, and 4) cysteine
supplementation may be a useful therapy if combined with
disease-specific treatments such as antiviral therapy in HIV infection.

Role of glutathione in nitric oxide-dependent regulation of energy
metabolism in rat hepatoma cells.
Nishikawa M; Sato EF; Kashiba M; Kuroki T; Utsumi K; Inoue M
Department of Biochemistry, Osaka City University Medical School,
Osaka, Japan.
Hepatology, 27(2):422-6 1998 Feb
Previous studies in this laboratory revealed that nitric oxide (NO)
reversibly inhibits the respiration of isolated mitochondria and
ascites hepatoma (AH-130) cells by an oxygen concentration-dependent
mechanism. The inhibitory effect of NO on the respiration of AH-130
cells was enhanced by treating with digitonin that selectively
permeabilized plasma membranes and released cytosolic
low-molecular-weight compounds. Reduced glutathione (GSH) is the most
abundant cytosolic thiol that easily reacts with NO. To elucidate the
mechanism by which digitonin enhanced the inhibitory action of NO, the
effect of GSH and related thiols was studied with AH-130 cells and
their mitochondria. The inhibitory effect of NO on the respiration of
digitonin-treated cells was suppressed by either GSH, L-cysteine, or
N-acetylcysteine, but not by oxidized glutathione. The inhibitory
effect of NO on the respiration of their mitochondria was also
decreased by GSH. In contrast, the inhibitory effect of NO was markedly
enhanced with AH-130 cells obtained from animals that were pretreated
with L-buthionine sulfoximine (BSO), a specific inhibitor for GSH
synthesis. Kinetic analysis revealed that NO dose-dependently decreased
GSH levels in AH-130 cells with concomitant generation of
S-nitrosothiols. Although S-nitrosoglutathione (GSNO), a slow releaser
of NO, also inhibited the respiration of tumor cell mitochondria, its
effect was significantly lower than that of NO. These results suggest
that cellular GSH might play pivotal roles in the regulation of energy
metabolism in hepatoma cells by modulating free forms of NO.

Alterations in renal cellular glutathione metabolism after in vivo
administration of a subtoxic dose of mercuric chloride.
Lash LH; Zalups RK
Department of Pharmacology' Wayne State University School of Medicine'
Detroit' MI 48201' USA.
J Biochem Toxicol, 11(1):1-9 1996
Renal cellular concentration of glutathione (GSH) increases after
exposure to a subtoxic dose of inorganic mercury (Hg2+). In the present
study' we tested the hypothesis that the increase in renal cellular
concentration of GSH after exposure to a subtoxic dose of Hg2+ (0.5
mumol HgCl2/kg body wt) is due to induction of GSH synthesis. Rats were
treated in vivo with HgCl2' and renal proximal tubular (PT) and distal
tubular (DT) cells were isolated 24 hours later. PT cells were studied
as the presumed target site for Hg2+' and DT cells were investigated as
a nontarget cell population. gamma-Glutamylcysteine synthetase activity
increased after exposure to Hg2+ in PT cells when expressed on a per
cell basis. Increases in activities of glutathione disulfide (GSSG)
reductase' GSH peroxidase' and several enzymes involved in cellular
energetics occurred after exposure to Hg2+. Many of these increases
were observed in both PT and DT cells' indicating that the responses to
Hg2+ were not restricted to the PT cells. These results are consistent
with the hypothesis that in vivo exposure to a subtoxic dose of Hg2+ is
also associated with induction of GSH synthesis and other key cellular
enzymes. Early changes in GSH metabolism associated with exposure to
Hg2+ appear to occur both in the primary target cell population and in
more distal nephron sites.

Effects of NO-generating compounds on synaptosomal energy metabolism.
Erecin]nska M; Nelson D; Vanderkooi JM
Department of Pharmacology' University of Pennsylvania' Philadelphia'
J Neurochem, 65(6):2699-705 1995 Dec
The effects of nitroprusside and S-nitrosocysteine' compounds that
generate nitric oxide (NO)' on synaptosomal energy-producing pathways
and energy level were investigated. The decrease in respiration was
much faster and more pronounced with S-nitrosocysteine than with
nitroprusside. S-Nitrosocysteine' at 10 microM' inhibited by 80%
respiration with glucose and succinate (plus rotenone) in intact
synaptosomes and with ascorbate/cytochrome c in broken preparations.
Oxygenated hemoglobin reversed and/or prevented the inhibition' whereas
glutathione (GSH) prolonged it. Under aerobic conditions' the
synaptosomal energy level (creatine phosphate/creatine and ATP/ADP
ratios) was reduced by the presence of S-nitrosocysteine' whereas
lactate generation was enhanced. The effects on energy parameters were
greater at 5 min than at 15 min of incubation and were more pronounced
in the presence of GSH. Under strictly anaerobic conditions' lactate
production was reduced by the NO-generating compounds in a
concentration-dependent manner. It is concluded that (a) inhibition of
oxidative phosphorylation by NO leads to a fall in the synaptosomal
energy level' which in turn stimulates glycolysis; (b) glycolysis can
be inhibited by higher concentrations of the radical; and (c)
inhibitory effects on the energy-generating pathway and ATP level could
contribute to NO toxicity under some in vivo situations.

Activities of enzymes involved in renal cellular glutathione metabolism
after uninephrectomy in the rat.
Lash LH; Zalups RK
Department of Pharmacology' Wayne State University School of Medicine'
Detroit' Michigan 48201.
Arch Biochem Biophys, 309(1):129-38 1994 Feb 15
The renal concentration of GSH increases after a significant reduction
in renal mass and compensatory renal growth. To test the hypothesis
that this increase is due to induction of GSH synthesis' the activities
of gamma-glutamylcysteine synthetase' other GSH-dependent enzymes' and
selected enzymes involved in cellular energetics were measured in
freshly isolated proximal tubular (PT) and distal tubular (DT) cells
from male Sprague-Dawley rats that underwent uninephrectomy and
compensatory renal growth or from sham-operated rats. Significant
increases in cellular content of protein without increases in
intracellular content of DNA' in both PT and DT cells' confirmed that
cellular hypertrophy had occurred. gamma-Glutamylcysteine synthetase
activity increased significantly in PT cells' but not in DT cells' as a
result of compensatory cellular hypertrophy' indicating that the
effects of cellular hypertrophy on GSH synthesis occurred exclusively
in the proximal tubule. Hypertrophy in PT cells' but not in DT cells'
was associated with significant increases in activities of glutathione
disulfide reductase' both Mg(2+)-dependent and (Na(+)+K+)-stimulated
ATPases' succinate:cytochrome c oxidoreductase' and lactate
dehydrogenase. Results from this study demonstrate that compensatory
hypertrophy occurs in both PT and DT cells and that effects on GSH
metabolism and cellular energetics associated with compensatory
hypertrophy are more pronounced in PT cells than in DT cells. The
findings also support our hypothesis that GSH synthesis is induced in
the proximal tubule during compensatory hypertrophy. The increase in
GSH synthesis may be an adaptive response to protect against oxidative
stress caused by increases in mitochondrial metabolism.

Altered energy metabolism and oxidative inJury following endotoxemia in
rats with normal or cirrhotic livers.
Ouchi K; Tanabe J; Tominaga T; Ito K; SaiJo S; Matsuno S
First Department of Surgery' Tohoku University School of Medicine'
Sendai' Japan.
Res Exp Med (Berl), 193(2):81-8 1993
The release of oxygen-derived free radicals has been implicated in
endotoxin-mediated hepatic inJury. The effect of hepatic lipid
peroxidation on tissue energy reserves in the livers of normal and
cirrhotic rats was studied following administration of E. coli
endotoxin. Before endotoxin inJection' the basal hepatic energy charge
was lower and levels of hepatic malondialdehyde (MDA) and total
glutathione (GSH) higher in cirrhotic rats than in normal rats.
Virtually identical levels of blood endotoxin were obtained in the two
groups 24 h after inJection of LD50 doses of endotoxin (20 mg/kg and 1
mg/kg in normal and cirrhotic rats' respectively). Hepatic energy
charge' tissue blood flow' GSH and glutathione peroxidase (GPX) were
consistently or transiently decreased up to 24 h after the inJection of
endotoxin in both normal and cirrhotic rats. MDA' significantly
increased in normal rats 1 h after inJection of endotoxin' returned to
normal levels 3-12 h after endotoxin administration' but was again
elevated at 24 h. Cirrhotic rats did not show any significant change in
MDA following endotoxin inJection. In normal rats' endotoxin appears to
trigger the liberation of free radicals accelerating depletion of
hepatic energy reserves' over and above the effect of decreased hepatic
blood flow. In contrast' increased lipid peroxidation was not detected
in cirrhotic rats despite GSH and GPX consumption during endotoxemia
(indicating oxygen radical generation). Cirrhotic livers were
apparently protected against oxygen radical inJury by higher levels of
endogenous GSH and GPX. Reduced hepatic blood flow may be mainly
responsible for the alteration in energy metabolism of the cirrhotic

The effects of a high dose of ascorbate on ischemia-reperfusion-induced
mitochondrial dysfunction in canine hearts.
Nishinaka Y; Sugiyama S; Yokota M; Saito H; Ozawa T
Department of Internal Medicine' Faculty of Medicine' University of
Nagoya' Japan.
Heart Vessels, 7(1):18-23 1992
The cardioprotective effects of a high dose of ascorbate on
ischemia-reperfusion-induced myocardial damage were investigated using
open chest anesthetized dogs. Two-hour occlusion of the left anterior
descending coronary artery (LAD) induced mitochondrial dysfunction with
a depletion of mitochondrial glutathione (GSH) concentration. Two-hour
LAD occlusion followed by 1-h reperfusion worsened the ischemia-induced
mitochondrial dysfunction together with a marked depletion of
mitochondrial GSH concentration. Ascorbate reduced the mitochondrial
dysfunction and prevented the depletion of mitochondrial GSH
concentration after 2-h LAD occlusion and 1-h reperfusion. Activities
of mitochondrial glutathione peroxidase and glutathione reductase did
not change significantly in each group. Administration of ascorbate
also prevented reperfusion arrhythmias without affecting blood pressure
or heart rate. These results suggest that coronary reperfusion induces
mitochondrial dysfunction and a depletion of mitochondrial GSH
concentration' and that a high dose of ascorbate prevents reperfusion

Impaired mitochondrial function, oxidative stress and altered
antioxidant enzyme activities following traumatic spinal cord injury.
Azbill RD; Mu X; Bruce-Keller AJ; Mattson MP; Springer JE
Department of Anatomy and Neurobiology, University of Kentucky Medical
Center, Lexington 40536-0084, USA.
Brain Res, 765(2):283-90 1997 Aug 15
Glutamate-induced excitotoxicity involving the formation of reactive
oxygen species (ROS) has been implicated in neuronal dysfunction and
cell loss following ischemic and traumatic injury to the central
nervous system (CNS). ROS are formed in mitochondria when energy
metabolism is compromised, and are inactivated by the ROS scavengers
superoxide dismutase (SOD), catalase, and glutathione (GSH). ROS can
impair the function of several cellular components including proteins,
nucleic acids, and lipids. In the present study, we measured indicators
of mitochondrial metabolic activity, ROS formation, lipid peroxidation,
and antioxidant enzyme activities in synaptosomes obtained from rat
spinal cord at early times following traumatic injury. Mitochondrial
metabolic activity was found to significantly decrease as early as 1 h
following injury, and continued to be compromised over the remaining
postinjury time points. ROS formation was found to be significantly
increased at 4 and 24 h following injury, while lipid peroxidation
levels were found to be significantly increased in the injured spinal
cord at 1 and 24 h, but not 4 h following injury. SOD enzyme activity
was unchanged at all postinjury time points, while catalase activity
and GSH levels were significantly increased at 24 h following injury.
These findings indicate that impaired mitochondrial function, ROS, and
lipid peroxidation occur soon after traumatic spinal cord injury, while
the compensatory activation of molecules important for neutralizing ROS
occurs at later time points. Therapeutic strategies aimed at
facilitating the actions of antioxidant enzymes or inhibiting ROS
formation and lipid peroxidation in the CNS may prove beneficial in
treating traumatic spinal cord injury, provided such treatments are
initiated at early stages following injury.

Effect of energy shortage and oxidative stress on amyloid precursor
protein metabolism in COS cells.
Gasparini L; Racchi M; Benussi L; Curti D; Binetti G; Bianchetti A;
Trabucchi M; Govoni S
A.Fa.R.' I.R.C.C.S San Giovanni di Dio' Alzheimer`s Disease Unit Sacred
Heart Hospital-FBF' Brescia' Italy.
Neurosci Lett, 231(2):113-7 1997 Aug 8
The present study investigates the influence of energy related
metabolic stress on amyloid precursor protein (APP) non-amyloidogenic
secretory processing in COS cells. The effect of glucose deprivation on
soluble APP (sAPP) secretion has been evaluated: incubation of COS
cells with 50 mM 2-deoxy-D-glucose (2-DG) in glucose free medium was
able to reduce sAPP secretion (-26%). Sodium azide (NaN3)' an inhibitor
of cytochrome c oxidase (complex IV of the mitochondrial electron
transfer chain) decreased sAPP release in a concentration dependent way
(maximum -75%). Treatment of COS cells with the antioxidant glutathione
(GSH) fully antagonized the inhibitory effect of azide (1 mM) and
elicited sAPP release over basal level. These results suggest that the
inhibition of energy metabolism can influence APP processing leading to
a decreased secretion of non-amyloidogenic fragments of APP.

Cultured AIDS-related Kaposi`s sarcoma (AIDS-KS) cells demonstrate
impaired bioenergetic adaptation to oxidant challenge: implication for
oxidant stress in AIDS-KS pathogenesis.
Mallery SR; Bailer RT; Hohl CM; Ng-Bautista CL; Ness GM; Livingston BE;
Hout BL; Stephens RE; Brierley GP
Department of Dentistry' College of Dentistry' Ohio State University'
Columbus 43210-1241' USA.
J Cell Biochem, 59(3):317-28 1995 Nov
Despite its recognition as the most prevalent HIV associated cancer'
speculation still abounds regarding the pathogenesis of AIDS-related
Kaposi`s sarcoma (AIDS-KS). However' it has been established that both
cytokines' e.g. IL-6' and HIV-associated products' e.g.' Tat' are
integral in AIDS-KS cellular proliferation. Further' both experimental
and clinical evidence is accumulating to link reactive oxygen
intermediates (ROI) with both cytokine induction (primarily via nuclear
factor-kappa B[NF-kappa B dependent routes) as well as the subsequent
cytokine' tumor necrosis factor alpha (TNF alpha) stimulation of HIV
replication. Features of AIDS-KS patients' such as retention of
phagocytes' presence of sustained immunostimulation' and a frequent
history of KS lesions arising at traumatized sites' make oxidant stress
a viable clinical factor in AIDS-KS development. Time course nucleotide
profile analyses show that AIDS-KS cells have an inherent'
statistically significant' biochemical deficit' even prior to oxidant
stress' due to 1) a more glycolytic bioenergetic profile' resulting in
lower levels of high energy phosphates (impairing capacity for
glutathione [GSH synthesis and DNA repair); 2) lower levels of NADPH
(compromising the activities of GSSG reductase and peroxidase function
of catalase); and 3) reduced levels of GSH (impeding both GSH
peroxidase and GSH-S-transferases). Following exposure to
physiologically relevant levels of H2O2' only the human microvascular
endothelial cells (a putative AIDS-KS progenitor cell) responded with
bioenergetic adaptations that reflected co-ordination of energy
generating and cytoprotective pathways' e.g.' retention of the cellular
energy charge' increased NAD+' and an accentuation of the ATP' NADPH'
and total adenine nucleotide differences relative to AIDS-KS cells.
Also' some of the AIDS-KS strains retained intracellular GSSG
subsequent to oxidant challenge' inviting the formation of deleterious
protein mixed disulfides. While the results of our study Address some
AIDS-KS issues' they also raise an etiological question' i.e.' Does the
inability to tolerate oxidant stress arise in conJunction with AIDS-KS
neoplastic development' or is it pre-existing in the population at
risk? Regardless' use of antioxidant therapy (low risk/ potentially
high benefit) in both the "at risk" population as well as in those
individuals with active disease may prove a useful preventative and/or
treatment modality.

glutathione depletion alters hepatocellular high-energy phosphate
Kobayashi T; Robinson MK; Robinson V; DeRosa E; Wilmore DW; Jacobs DO
Laboratory for Surgical Metabolism' Brigham and Women`s Hospital'
Boston' Massachusetts.
J Surg Res, 54(3):189-95 1993 Mar
Oxygen free radicals have recently been implicated as a maJor cause of
tissue inJury in critically ill patients. glutathione (GSH) is a potent
endogenous antioxidant that may be important in minimizing
oxidant-induced organ damage. However' this tripeptide is depleted
during severe illness. In order to determine the effect of GSH
depletion on hepatic high-energy phosphate metabolism' in vivo 31P
magnetic resonance spectroscopy was used to measure phosphate ratios in
male Wistar rats given 1 ml/kg of diethylmaleate (DEM)' an agent that
binds and thus depletes tissue GSH' or corn oil vehicle
intraperitoneally. Spectra of the liver were obtained in noninJected
animals (baseline' n = 15) and in rats 2 and 24 hr after the
intraperitoneal inJection of DEM (n = 20) or corn oil (control' n =
20). These spectra were used to measure hepatocellular pH'
phosphomonoester to ATP (PME/ATP)' and phosphodiester to ATP ratios'
measures of hepatocellular damage; and the inorganic phosphate (Pi)/ATP
ratio' a measure of energy status. In addition' tissue GSH'
phosphofructokinase' citrate synthase' and beta-OH-acyl-Co-A
dehydrogenase activities as well as hepatocellular ATP were measured in
vitro in representative liver samples. Hepatic GSH levels were
maximally depressed by 85% 2 hr after the inJection of DEM (6.94 +/-
0.34 vs 0.94 +/- 0.22 microM/g wet wt' baseline vs 2 degrees DEM). This
was associated with a marked increase in the PME/ATP and Pi/ATP ratios
by 25 and 33%' respectively' and both ratios were significantly
correlated with the severity of hepatic GSH depletion (r = 0.63' P <
0.001 and r = 0.42' P < 0.01' respectively).(Abstract TRUNCATED AT 250

Cellular reducing equivalents and oxidative stress.
Kehrer JP; Lund LG
Division of Pharmacology/Toxicology' College of Pharmacy' University of
Texas at Austin.
Free Radic Biol Med, 17(1):65-75 1994 Jul
energy has been proposed to play a role in the ability of cells and
tissues to defend against oxidative stress' even though the ultimate
antioxidant capacity of a tissue is determined by the supply of
reducing equivalents. The pathways involved in supplying reducing
equivalents in response to an oxidative stress remain unclear'
particularly if competing reactions such as ATP synthesis are active.
glutathione (GSH)' a maJor component of cellular antioxidant systems'
is maintained in the reduced form by glutathione reductase. Although
this enzyme is specific for NADPH' the ability of intact cells'
isolated mitochondria (which are a maJor Source of free radicals and
contain antioxidant systems independent of the rest of the cell)' and
whole tissues to supply reducing equivalents and maintain normal levels
of GSH appears to involve NADH. This article reviews available data
regarding the Source and pathways by which reducing equivalents are
made available to reduce exogenous oxidants' and suggests energy is not
a factor. An improved understanding of the mechanism by which reducing
equivalents are supplied by tissues to respond to an oxidative stress
may direct future research toward designing strategies for augmenting
the ability of tissues to defend themselves against oxidative stress
induced by reperfusion or xenobiotics.

Age and GSH metabolism in rat cerebral cortex' as related to oxidative
and energy parameters [published erratum appears in Mech Ageing Dev
1993 Dec 31;72(3):231
Iantomasi T; Favilli F; Marraccini P; Stio M; Treves C; Quattrone A;
Capaccioli S; Vincenzini MT; Quatrone A [corrected to Quattrone A
Department of Biochemical Sciences' University of Florence' Italy.
Mech Ageing Dev, 70(1-2):65-82 1993 Aug 1
A comprehensive study on GSH metabolism in relation to some markers of
oxidative and energy status in rat cerebral cortex as a function of age
was performed. Reduced GSH' total GSH and the GSH Redox Index decreased
both during growth (defined as the period between 1 and 5 months) and
during aging (defined as the period between 5 and 27 months) while GSSG
levels increased during the two periods' but most significantly during
aging. Also GSH-associated enzymes and adenine-pyridine nucleotide
levels show age characteristic changes. The obtained results suggest
that decreases in oxidative and energy metabolism occur during aging.
They probably contribute to decreases in the activity of the
biosynthetic processes (i.e.' NADP+(H) and GSH synthesis) and in the
antioxidant capacity of the GSH system. However' the oxidative stress
does not seem to be a typical characteristic of the aging period; as an
oxidative status is present during the growth period too. Typical
parameters of aging process are mainly the low levels of reduced GSH'
total GSH and GSH Redox Index and the high levels of GSSG as well as
the high levels of GSH peroxidase and GSH transferase and the low
levels of gamma-glutamylcysteine synthetase.


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