Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals : Inhibition of α-ketoglutarate dehydrogenase

Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rote...

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Veröffentlicht in:Journal of neurochemistry 1999-07, Vol.73 (1), p.220-228
Hauptverfasser: CHINOPOULOS, C, TRETTER, L, ADAM-VIZI, V
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TRETTER, L
ADAM-VIZI, V
description Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.
doi_str_mv 10.1046/j.1471-4159.1999.0730220.x
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Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. 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Psychology ; Guinea Pigs ; Hydrogen Peroxide - pharmacology ; Intracellular Membranes - physiology ; Ketoglutarate Dehydrogenase Complex - antagonists &amp; inhibitors ; Membrane Potentials - drug effects ; Mitochondria - ultrastructure ; NADP - metabolism ; Nerve Endings - ultrastructure ; Oligomycins - pharmacology ; Oxidative Stress - drug effects ; Oxidative Stress - physiology ; Proton-Translocating ATPases - antagonists &amp; inhibitors ; Rotenone - pharmacology ; Spectrometry, Fluorescence ; Synaptosomes - ultrastructure ; Uncoupling Agents - pharmacology ; Vertebrates: nervous system and sense organs</subject><ispartof>Journal of neurochemistry, 1999-07, Vol.73 (1), p.220-228</ispartof><rights>1999 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c318t-30afbcaa41e02e1f0f51e968add470f2a3a04202cad3f168384f4feb879127853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=1887577$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10386974$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CHINOPOULOS, C</creatorcontrib><creatorcontrib>TRETTER, L</creatorcontrib><creatorcontrib>ADAM-VIZI, V</creatorcontrib><title>Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals : Inhibition of α-ketoglutarate dehydrogenase</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.</description><subject>a-Ketoglutarate dehydrogenase</subject><subject>Animals</subject><subject>Benzimidazoles</subject><subject>Biological and medical sciences</subject><subject>Carbocyanines</subject><subject>Central nervous system</subject><subject>Cerebral Cortex - ultrastructure</subject><subject>Electrophysiology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fluorescent Dyes</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Guinea Pigs</subject><subject>Hydrogen Peroxide - pharmacology</subject><subject>Intracellular Membranes - physiology</subject><subject>Ketoglutarate Dehydrogenase Complex - antagonists &amp; inhibitors</subject><subject>Membrane Potentials - drug effects</subject><subject>Mitochondria - ultrastructure</subject><subject>NADP - metabolism</subject><subject>Nerve Endings - ultrastructure</subject><subject>Oligomycins - pharmacology</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxidative Stress - physiology</subject><subject>Proton-Translocating ATPases - antagonists &amp; inhibitors</subject><subject>Rotenone - pharmacology</subject><subject>Spectrometry, Fluorescence</subject><subject>Synaptosomes - ultrastructure</subject><subject>Uncoupling Agents - pharmacology</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1u1DAUxy0EokPhCshCiF2CnTix0x0qX5UqsYG19SZ-7njI2IPtVFOOwi24CGfC0UyBHSvr2f8P-f0IecFZzZnoX29rLiSvBO-Gmg_DUDPZsqZh9eEBWf15ekhWrNxWLRPNGXmS0pYx3ouePyZnnLWqH6RYkR9vcR8miO47ZBc8DZY6T5PLM925HMZN8CY6oGZGmgPd3JkYbtDTPcZwcAYr5808oqHLVCJukaYcMaUlxmMsc8a4cx6mRC_old-4tbtv-vWz-oo53ExzhggZqcH7Akj4lDyyxYXPTuc5-fL-3efLj9X1pw9Xl2-uq7HlKpf_gV2PAIIja5BbZjuOQ6_AGCGZbaCFsgHWjGBay3vVKmGFxbWSA2-k6tpz8uqYu4_h24wp651LI04TeAxz0v2gur4T4r9CLgUr61dFeHEUjjGkFNHqfXQ7iHeaM70g1Fu9cNILJ70g1CeE-lDMz08t83qH5h_rkVkRvDwJII0w2Qh-dOmvTinZSdn-BotEqeA</recordid><startdate>19990701</startdate><enddate>19990701</enddate><creator>CHINOPOULOS, C</creator><creator>TRETTER, L</creator><creator>ADAM-VIZI, V</creator><general>Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>19990701</creationdate><title>Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals : Inhibition of α-ketoglutarate dehydrogenase</title><author>CHINOPOULOS, C ; TRETTER, L ; ADAM-VIZI, V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c318t-30afbcaa41e02e1f0f51e968add470f2a3a04202cad3f168384f4feb879127853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>a-Ketoglutarate dehydrogenase</topic><topic>Animals</topic><topic>Benzimidazoles</topic><topic>Biological and medical sciences</topic><topic>Carbocyanines</topic><topic>Central nervous system</topic><topic>Cerebral Cortex - ultrastructure</topic><topic>Electrophysiology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Fluorescent Dyes</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Guinea Pigs</topic><topic>Hydrogen Peroxide - pharmacology</topic><topic>Intracellular Membranes - physiology</topic><topic>Ketoglutarate Dehydrogenase Complex - antagonists &amp; inhibitors</topic><topic>Membrane Potentials - drug effects</topic><topic>Mitochondria - ultrastructure</topic><topic>NADP - metabolism</topic><topic>Nerve Endings - ultrastructure</topic><topic>Oligomycins - pharmacology</topic><topic>Oxidative Stress - drug effects</topic><topic>Oxidative Stress - physiology</topic><topic>Proton-Translocating ATPases - antagonists &amp; inhibitors</topic><topic>Rotenone - pharmacology</topic><topic>Spectrometry, Fluorescence</topic><topic>Synaptosomes - ultrastructure</topic><topic>Uncoupling Agents - pharmacology</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHINOPOULOS, C</creatorcontrib><creatorcontrib>TRETTER, L</creatorcontrib><creatorcontrib>ADAM-VIZI, V</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHINOPOULOS, C</au><au>TRETTER, L</au><au>ADAM-VIZI, V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals : Inhibition of α-ketoglutarate dehydrogenase</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>1999-07-01</date><risdate>1999</risdate><volume>73</volume><issue>1</issue><spage>220</spage><epage>228</epage><pages>220-228</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.</abstract><cop>Oxford</cop><pub>Blackwell</pub><pmid>10386974</pmid><doi>10.1046/j.1471-4159.1999.0730220.x</doi><tpages>9</tpages></addata></record>
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subjects a-Ketoglutarate dehydrogenase
Animals
Benzimidazoles
Biological and medical sciences
Carbocyanines
Central nervous system
Cerebral Cortex - ultrastructure
Electrophysiology
Enzyme Inhibitors - pharmacology
Fluorescent Dyes
Fundamental and applied biological sciences. Psychology
Guinea Pigs
Hydrogen Peroxide - pharmacology
Intracellular Membranes - physiology
Ketoglutarate Dehydrogenase Complex - antagonists & inhibitors
Membrane Potentials - drug effects
Mitochondria - ultrastructure
NADP - metabolism
Nerve Endings - ultrastructure
Oligomycins - pharmacology
Oxidative Stress - drug effects
Oxidative Stress - physiology
Proton-Translocating ATPases - antagonists & inhibitors
Rotenone - pharmacology
Spectrometry, Fluorescence
Synaptosomes - ultrastructure
Uncoupling Agents - pharmacology
Vertebrates: nervous system and sense organs
title Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals : Inhibition of α-ketoglutarate dehydrogenase
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