Hyperoxia-induced clonogenic killing of HeLa cells associated with respiratory failure and selective inactivation of Krebs cycle enzymes

Scoonen, W.G.E.J.; Wanamarta, A.Handayani; Moorsel, J.M. van der Kle-van; Jakobs, Cornelis; Joejne, H.

doi:10.1016/0921-8734(90)90023-k

Cited by 44 publications

(26 citation statements)

References 28 publications

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“…Inactivation of the pyruvate dehydrogenase complex after ischemia supports this view (Bogaert et a!., 1994) and agrees with the notion that mitochondna! Krebs cycle enzymes are susceptible to ROS damage (Schoonen et al, 1990).…”

Section: Molecular Response Of Kgdhc To Tdmentioning

confidence: 99%

Immunochemical Characterization of the Deficiency of the α‐Ketoglutarate Dehydrogenase Complex in Thiamine‐Deficient Rat Brain

Sheu

Calingasan

Lindsay

et al. 1998

Journal of Neurochemistry

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Abstract:Mitochondrial dysfunction is a common feature of many neurodegenerative disorders. The metabolic encephalopathy caused by thiamine deficiency (TD) is a classic example in which an impairment of cerebral oxidative metabolism leads to selective cell death. In experimental TD in rodents, a reduction in the activity of the thiamine diphosphate-dependent, mitochondrial enzyme a-ketoglutarate dehydrogenase complex (KGDHC) occurs before the onset of pathologic lesions and is among the earliest biochemical deficits found. To understand the molecular basis and the significance of the deficiency of KGDHC in TD-induced brain damage, the enzyme activity and protein levels of KGDHC were analyzed. The effect of TD on the subregional/cellular distribution of KGDHC and the anatomic relation of KGDHC with selective cell death were also tested by immunocytochemistry. Consistent with several previous studies, TD dramatically reduced KGDHC activity in both anatomically damaged (thalamus and inferior colliculus) and spared (cerebral cortex) regions. Immunocytochemistry revealed no apparent correlation of regional KGDHC immunoreactivity or its response to TD with affected regions in TD. The basis of the enzymatic and immunocytochemical behavior of KGDHC was further assessed by quantitative immunoblots, using antibodies specific for each of the three KGDHC components. Despite the marked decrease of KGDHC activity in TD, no reduction of any of the three KGDHC protein levels was found. Thus, TD impairs the efficacy of the KGDHC catalytic machinery, whereas the concentration of protein molecules persists. The generalized decline of KGDHC activity with no apparent anatomic selectivity is consistent with the notion that the compromised mitochondrial oxidation sensitizes the brain cells to various other insults that precipitate the cell death. The current TD model provides a relevant experimental system to understand the molecular basis of many neurodegenerative conditions in which mitochondrial dysfunction and KGDHC deficiency are prominent features. Key Words: Alzheimer's disease-et-Ketoglutarate dehydrogenase-2-Oxoglutarate dehydrogenaseOxidative stress-Thiamine deficiency-Thiamine diphosphate-dependent enzymes-Wernicke-Korsakoff's syndrome.

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Section: Molecular Response Of Kgdhc To Tdmentioning

confidence: 99%

Immunochemical Characterization of the Deficiency of the α‐Ketoglutarate Dehydrogenase Complex in Thiamine‐Deficient Rat Brain

Sheu

Calingasan

Lindsay

et al. 1998

Journal of Neurochemistry

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“…For example, the metabolic rate of army worm pupae (Prodenia eridania) exposed to hyperbaric hyperoxia was reduced 20-to 50-fold relative to normoxic controls (Clark and Cristofalo, 1960). Mammalian cell cultures exposed to hyperoxia also show large (approximately threefold) decreases in metabolic rate compared with normoxic cells (Schoonen et al, 1990).…”

Section: Effects Of 100% O 2 On Metabolic Ratementioning

confidence: 99%

“…Studies in mammalian cells in culture have found that hyperoxia can inactivate many enzymes crucial to normal metabolic function (Gardner et al, 1994;Joenje, 1989). Functional consequences of such changes include protein misfolding, catalytic inactivation, the loss of protein functions and a reduction in the function of glycolysis and the tricarboxylic (TCA) acid cycle (Das et al, 2001;Schoonen et al, 1990;Yan et al, 1997;Yan and Sohal, 1998). Hyperoxia can also increase rates of oxidation of pyridine nucleotides (NAD and NADH), significantly increasing ROS production from mitochondria, as well as damage to mitochondria (Arthur et al, 1997;Gille and Joenje, 1992;Wispe et al, 1992).…”

Section: Effects Of 100% O 2 On Metabolic Ratementioning

confidence: 99%

“…Hyperoxia toxicity is thought to be caused by an increased production of free radicals and hydrogen peroxide generation (Joenje, 1989;Paget et al, 1987). Among other effects, hyperoxia can disrupt metabolic pathways and reduce respiration rates (Gille and Joenje, 1992;Jamieson, 1989;Schoonen et al, 1990). Humans exposed to pure O 2 for more than 24 h begin to show compromised lung function and exposure to several days of pure O 2 is lethal to many mammals and insects (Mockett et al, 2001;Smith and Gottlieb, 1975).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic function inDrosophila melanogasterin response to hypoxia and pure oxygen

Voorhies

2009

Journal of Experimental Biology

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SUMMARYThis study examined the metabolic response of Drosophila melanogaster exposed to O 2 concentrations ranging from 0 to 21% and at 100%. The metabolic rate of flies exposed to graded hypoxia remained nearly constant as O 2 tensions were reduced from normoxia to ~3 kPa. There was a rapid, approximately linear reduction in fly metabolic rate at P O2 s between 3 and 0.5 kPa. The reduction in metabolic rate was especially pronounced at P O2 levels <0.5 kPa, and at a P O2 of 0.1 kPa fly metabolic rate was reduced ~10-fold relative to normoxic levels. The metabolic rate of flies exposed to anoxia and then returned to normoxia recovered to pre-anoxic levels within 30 min with no apparent payment of a hypoxia-induced oxygen debt. Flies tolerated exposure to hypoxia and/or anoxia for 40 min with nearly 100% survival. Fly mortality increased rapidly after 2 h of anoxia and >16 h exposure was uniformly lethal. Flies exposed to pure O 2 for 24 h showed no apparent alteration of metabolic rate, even though such O 2 tensions should damage respiratory enzymes critical to mitochondria function. Within a few hours the metabolic rate of flies recovering from exposure to repeated short bouts of anoxia was the same as flies exposed to a single anoxia exposure.

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“…Recent studies show that KGDHC in cells is more sensitive to oxidative stress, than fluorescent probes that are used to measure ROS (Zhang et al, 2000). Hyperoxia, which causes excess ROS production, totally inactivates KGDHC in CHO cells, whereas other mitochondrial enzymes are much less sensitive (Schoonen et al, 1990). The reactive aldehyde 4-hydroxynonenal (HNE) is cytotoxic and reduces the activity of isolated KGDHC (Park and Gibson, unpublished results), as well as mitochondrial KGDHC (Humphries et al, 1998).…”

Section: Discussionmentioning

confidence: 95%

Mitochondrial impairment in the cerebellum of the patients with progressive supranuclear palsy

Park

Albers

et al. 2001

J of Neuroscience Research

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Abnormalities in energy metabolism and oxidative stress accompany many neurodegenerative diseases, including progressive supranuclear palsy (PSP). Previously, we showed decreased activities of a mitochondrial enzyme complex, alpha-ketoglutarate dehydrogenase complex (KGDHC), and marked increases in tissue malondialdehyde levels in post-mortem superior frontal cortex from the patients with PSP. The current study demonstrates that KGDHC is also significantly diminished (-58%) in the cerebellum from patients with PSP (n = 14), compared to age-matched control brains (n = 13). In contrast to cortex, markers of oxidative stress, such as malondialdehyde, tyrosine nitration or general protein carbonyl modification, did not increase in cerebellum. Furthermore, the protein levels of the individual components of KGDHC did not decline. The activities of two other mitochondrial enzymes were measured to determine whether the changes in KGDHC were selective. The activity of aconitase, a mitochondrial enzyme with an iron/sulfur cluster, is also significantly diminished (-50%), whereas glutamate dehydrogenase activity is unchanged. The present results suggest that the interaction of metabolic impairment and oxidative stress is region-specific in PSP brain. In cerebellum, reductions in KGDHC occur in the absence of increases in common measures of oxidative stress, and may underlie the metabolic deficits and contribute to pathological and clinical manifestation related to the cerebellum in patients with PSP.

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Hyperoxia-induced clonogenic killing of HeLa cells associated with respiratory failure and selective inactivation of Krebs cycle enzymes

Cited by 44 publications

References 28 publications

Immunochemical Characterization of the Deficiency of the α‐Ketoglutarate Dehydrogenase Complex in Thiamine‐Deficient Rat Brain

Immunochemical Characterization of the Deficiency of the α‐Ketoglutarate Dehydrogenase Complex in Thiamine‐Deficient Rat Brain

Metabolic function inDrosophila melanogasterin response to hypoxia and pure oxygen

Mitochondrial impairment in the cerebellum of the patients with progressive supranuclear palsy

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