12 December 2008
complex I, hydrogen peroxide, mitochondrion, reactive oxygen species (ROS), respiratory chain, superoxide, CoQ, coenzyme Q, CoQH2, reduced CoQ, DPI, diphenyleneiodonium, ETF, electron transfer flavoprotein, α-GPDH, α-glycerophosphate dehydrogenase, HIF-1, hypoxia-inducible factor-1, αKGDH, 2-oxoglutarate dehydrogenase (α-ketoglutarate dehydrogenase), PHD, prolyl hydroxylase, RET, reverse electron transport, ROS, reactive oxygen species, SMP, submitochondrial particle, SOD, superoxide dismutase
The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O 2 •−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O 2 •− production within the matrix of mammalian mitochondria. The flux of O 2 •− is related to the concentration of potential electron donors, the local concentration of O 2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O 2 •− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD + ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD + ratio, the extent of O 2 •− production is far lower. The generation of O 2 •− within the mitochondrial matrix depends critically on Δp, the NADH/NAD + and CoQH 2/CoQ ratios and the local O 2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O 2 •− generation by mitochondria in vivo from O 2 •−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O 2 •− and H 2O 2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.