Modulation of mitochondrial function by hydrogen peroxide.
During normal cellular metabolism, mitochondrial electron transport results in the formation of superoxide anion (O(2)) and subsequently hydrogen peroxide (H(2)O(2)). Because H(2)O(2) increases in concentration under certain physiologic and pathophysiologic conditions and can oxidatively modify cellular components, it is critical to understand the response of mitochondria to H(2)O(2). In the present study, treatment of isolated rat heart mitochondria with H(2)O(2) resulted in a decline and subsequent recovery of state 3 NADH-linked respiration. Alterations in NADH levels induced by H(2)O(2) closely paralleled changes in the rate of state 3 respiration. Assessment of electron transport chain complexes and Krebs cycle enzymes revealed that alpha-ketoglutarate dehydrogenase (KGDH), succinate dehydrogenase (SDH), and aconitase were susceptible to H(2)O(2) inactivation. Of particular importance, KGDH and SDH activity returned to control levels, concurrent with the recovery of state 3 respiration. Inactivation is not because of direct interaction of H(2)O(2) with KGDH and SDH. In addition, removal of H(2)O(2) alone is not sufficient for reactivation. Enzyme activity does not recover unless mitochondria remain intact. The sensitivity of KGDH and SDH to H(2)O(2)-mediated inactivation and the reversible nature of inactivation suggest a potential role for H(2)O(2) in the regulation of KGDH and SDH.
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970, USA.
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Nulton-Persson
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Szweda
D000818:Animals; D019069:Cell Respiration; D002952:Citric Acid Cycle / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D007700:Kinetics; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D009249:NADP / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D016877:Oxidants; D009249:NADP; D006861:Hydrogen Peroxide; D007655:Ketoglutarate Dehydrogenase Complex; D013385:Succinate Dehydrogenase