Succinate modulation of H2O2 release at NADH:ubiquinone oxidoreductase (Complex I) in brain mitochondria

Abstract

Complex I (NADH:ubiquinone oxidoreductase) is responsible for most of the mitochondrial H2O2 release, both during the oxidation of NAD-linked substrates and during succinate oxidation. The much faster succinate-dependent H2O2 production is ascribed to Complex I, being rotenone-sensitive. In the present paper, we report high-affinity succinate-supported H2O2 generation in the absence as well as in the presence of GM (glutamate/malate) (1 or 2 mM of each). In brain mitochondria, their only effect was to increase from 0.35 to 0.5 or to 0.65 mM the succinate concentration evoking the semi-maximal H2O2 release. GM are still oxidized in the presence of succinate, as indicated by the oxygen-consumption rates, which are intermediate between those of GM and of succinate alone when all substrates are present together. This effect is removed by rotenone, showing that it is not due to inhibition of succinate influx. Moreover, alpha-oxoglutarate production from GM, a measure of the activity of Complex I, is decreased, but not stopped, by succinate. It is concluded that succinate-induced H2O2 production occurs under conditions of regular downward electron flow in Complex I. Succinate concentration appears to modulate the rate of H2O2 release, probably by controlling the hydroquinone/quinone ratio.

Role of Neuronal Mitochondrial Metabolic Phenotype in Pathogenesis of ALS

“…This process, known as reverse electron transport, is energy-dependent and inhibited by rotenone. Some researchers deny the significance of succinate in ROS production on the pretext that succinate concentration is too low in mitochondria (Starkov, 2008;Stowe & Camara, 2009;Zoccarato et al, 2007). As we have shown recently, however, brain and spinal cord mitochondria may produce succinate even in the presence of pyruvate + malate (Panov et al, 2009) , and as we show in this article (see Fig.…”

Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

“…It is coupled to proton pumping, specifically pumping four protons across the inner mitochondrial membrane, from the matrix to the intermembrane space, thus contributing to the proton gradient that will later fuel the ATP synthase (239). Complex I is the major site of the premature leak of electrons to oxygen, thereby creating the free radical superoxide (469). Complex III contains two pools of ubiquinone: Q i faces the mitochondrial matrix and Q 0 faces the intermembrane space (93,394).…”

Mitochondrial Signaling in Hypoxia

“…This process is associated with activation of MtC II (SDH) and increased contribution of succinate oxidation to cell respiration; this contribution may reach 70% -80% [4,[6][7][8][9][10][11][16][17][18][19]21,22,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41].…”