Modulation of Mitochondrial Function by Hydrogen Peroxide

During normal cellular metabolism, mitochondrial electron transport results in the formation of superoxide anion (O₂^.-) and subsequently hydrogen peroxide (H₂O₂). Because H ₂O₂ 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 H₂O ₂. In the present study, treatment of isolated rat heart mitochondria with H₂O₂ resulted in a decline and subsequent recovery of state 3 NADH-linked respiration. Alterations in NADH levels induced by H₂O₂ closely paralleled changes in the rate of state 3 respiration. Assessment of electron transport chain complexes and Krebs cycle enzymes revealed that α-ketoglutarate dehydrogenase (KGDH), succinate dehydrogenase (SDH), and aconitase were susceptible to H ₂O₂ 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 ₂O₂ with KGDH and SDH. In addition, removal of H ₂O₂ alone is not sufficient for reactivation. Enzyme activity does not recover unless mitochondria remain intact. The sensitivity of KGDH and SDH to H₂O₂-mediated inactivation and the reversible nature of inactivation suggest a potential role for H ₂O₂ in the regulation of KGDH and SDH.