Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions

Abstract

Mitochondrial production of superoxide and hydrogen peroxide is potentially important in cell signaling and disease. Eleven distinct mitochondrial sites that differ markedly in capacity are known to leak electrons to oxygen to produce O₂^̇̄ and/or H₂O₂ We discuss their contributions to O₂^̇̄/H₂O₂ production under native conditions in mitochondria oxidizing different substrates and in conditions mimicking physical exercise and the changes in their capacities after caloric restriction. We review the use of S1QELs and S3QELs, suppressors of mitochondrial O₂^̇̄/H₂O₂ generation that do not inhibit oxidative phosphorylation, as tools to characterize the contributions of specific sites in situ and in vivo.

Keywords: Complex I; complex III; hydrogen peroxide; mitochondria; reactive oxygen species (ROS); superoxide ion.

Figure 1.

Mitochondrial sites of O₂^˙̄/H₂O₂ production. Eleven distinct mitochondrial sites that leak electrons to oxygen to produce superoxide and/or hydrogen peroxide during substrate oxidation have been identified (21, 25–28, 30–33). Yellow circles indicate flavin groups, and orange circles indicate quinone-binding sites of enzymes and complexes. ETF, electron-transferring flavoprotein; ETF:QOR, electron-transferring flavoprotein-ubiquinone oxidoreductase; QH₂, ubiquinol; Q, ubiquinone. Sites O_F, B_F, A_F, P_F, I_F, I_Q, II_F, III_Qo, G_Q, E_F, and D_Q refer to the flavin (subscript F) or ubiquinone-binding sites (subscript Q) of the 2-oxoglutarate (O), branched chain 2-oxoacid (B), 2-oxoadipate (A), and pyruvate (P) dehydrogenase complexes, of complex I, complex II, and the outer ubiquinone site of complex III (III_Qo), and of mitochondrial glycerol-3-phosphate dehydrogenase (G), the ETF/ETF:QOR system (E), and dihydroorotate dehydrogenase (D).

Figure 2.

Relative contributions of specific sites of O₂^˙̄/H₂O₂ production to total H₂O₂ production by isolated rat muscle mitochondria under different bioenergetic conditions. The diameters of the pie charts are proportional to the total rates of mitochondrial H₂O₂ production. Total rates of mitochondrial H₂O₂ production (pmol of H₂O₂ min⁻¹ mg protein⁻¹) were ∼890 (succinate), ∼620 (glycerol 3-phosphate), ∼200 (palmitoylcarnitine), ∼180 (glutamate plus malate), ∼340 (rest), ∼80 (mild aerobic exercise), and ∼50 (intense aerobic exercise). Data are from Refs. and .