Role of ubiquinone in the mitochondrial generation of hydrogen peroxide

Abstract

Antimycin-inhibited bovine heart submitochondrial particles generate O2- and H2O2 with succinate as electron donor. H2O2 generation involves the action of the mitochondrial superoxide dismutase, in accordance with the McCord & Fridovich [(1969) j. biol. Chem. 244, 6049-6055] reaction mechanism. Removal of ubiquinone by acetone treatment decreases the ability of mitochondrial preparations to generate O2- and H2O2, whereas supplementation of the depleted membranes with ubiquinone enhances the peroxide-generating activity in the reconstituted membranes. Addition of superoxide dismutase to ubiquinone-reconstituted membranes is essential in order to obtain maximal rates of H2O2 generation since the acetone treatment of the membranes apparently inactivates (or removes) the mitochondrial superoxide dismutase. Parallel measurements of H2O2 production, succinate dehydrogenase and succinate-cytochrome c reductase activities show that peroxide generation by ubiquinone-supplemented membranes is a monotonous function of the reducible ubiquinone content, whereas the other two measured activities reach saturation at relatively low concentrations of reducible quinone. Alkaline treatment of submitochondrial particles causes a significant decrease in succinate dehydrogenase activity and succinate-dependent H2O2 production, which contrasts with the increase of peroxide production by the same particles with NADH as electron donor. Solubilized succinate dehydrogenase generates H2O2 at a much lower rate than the parent submitochondrial particles. It is postulated that ubisemiquinone (and ubiquinol) are chiefly responsible for the succinate-dependent peroxide production by the mitochondrial inner membrane.

Mitochondrial complex III regulates hypoxic activation of HIF

“…41,43,[47][48][49] Unlike complexes I and II, which generate superoxide into the mitochondrial matrix, [52][53][54][55] complex III can also release superoxide into the mitochondrial intermembrane space and subsequently, into the cytosol. [56][57][58] The Q cycle is initiated when complex I and complex II transfer electrons to reduce the lipid moiety ubiquinone to ubiquinol (Figure 3). Ubiquinol then enters the Q cycle (Figure 3).…”

Mitochondrial involvement in neurodegenerative diseases

“…Within the respiratory chain complex I, the FMN moiety (31,32), iron-sulfur clusters (33,34), and semiquinones (35) have been suggested to be responsible for mitochondrial superoxide production. For respiratory chain complex III, the semiquinone at center ''o'' of the Q-cycle (being stabilized by antimycin A treatment) has been identified as an additional site of mitochondrial superoxide production (36), which in contrast to complex I releases superoxide to the intermembrane space (37,38). While under conditions of inhibited electron transfer (e.g., under conditions of cytochrome c release), all these sites are potentially relevant, the relevance of the latter site under the conditions of uninhibited electron flow is still a matter of discussion (39,40).…”

Application of capillary isotachophoresis‐based multidimensional separations coupled with electrospray ionization‐tandem mass spectrometry for characterization of mouse brain mitochondrial proteome

“…Alteration of the mitochondrial proteome and altered mitochondrial function has been implicated in a variety of degenerative diseases, heart disease, aging, and cancer [2][3][4][5][6][7]. Because the mitochondria are a major source of endogenously generated reactive oxygen species (ROS), it is not surprising that they have been proposed to play a major role in aging [8,9]. The free radical theory of aging predicts that oxidative damage to the mitochondria can lead to an amplifying effect whereby damaged mitochondria release more ROS, further increasing oxidative damage [10].…”