fumarates and ubiquinol

For electrons to continuously enter and flow through the mitochondrial electron transport chain (ETC), they must ultimately land on a terminal electron acceptor (TEA), which is known to be oxygen in mammals. Paradoxically, we find that complex I and dihydroorotate dehydrogenase (DHODH) can still deposit electrons into the ETC when oxygen reduction is impeded. Cells lacking oxygen reduction accumulate ubiquinol, driving the succinate dehydrogenase (SDH) complex in reverse to enable electron deposition onto fumarate. Upon inhibition of oxygen reduction, fumarate reduction sustains DHODH and complex I activities. Mouse tissues display varying capacities to use fumarate as a TEA, most of which net reverse the SDH complex under hypoxia. Thus, we delineate a circuit of electron flow in the mammalian ETC that maintains mitochondrial functions under oxygen limitation.

Topics: Animals; Cell Hypoxia; Cell Line; Cell Line, Tumor; Dihydroorotate Dehydrogenase; Electron Transport; Electron Transport Complex I; Electron Transport Complex III; Electron Transport Complex IV; Electrons; Female; Fumarates; Humans; Mice; Mice, Inbred C57BL; Mitochondria; Oxidation-Reduction; Oxygen; Succinate Dehydrogenase; Ubiquinone

O2- generation in mitochondrial electron transport systems, especially the NADPH-coenzyme Q10 oxidoreductase system, was examined using a model system, NADPH-coenzyme Q1-NADPH-dependent cytochrome P-450 reductase. One electron reduction of coenzyme Q1 produces coenzyme Q1-. and O2- during enzyme-catalyzed reduction and O2+ coenzyme Q1-. are in equilibrium with O2- + coenzyme Q1 in the presence of enough O2. The coenzyme Q1-. produced can be completely eliminated by superoxide dismutase, identical to bound coenzyme Q10 radical produced in a succinate/fumarate couple-KCN-submitochondrial system in the presence of O2. Superoxide dismutase promotes electron transfer from reduced enzyme to coenzyme Q1 by the rapid dismutation of O2- generated, thereby preventing the reduction of coenzyme Q1 by O2-. The enzymatic reduction of coenzyme Q1 to coenzyme Q1H2 via coenzyme Q1-. is smoothly achieved under anaerobic conditions. The rate of coenzyme Q1H2 autoxidation is extremely slow, i.e., second-order constant for [O2][coenzyme Q1H2] = 1.5 M-1.s-1 at 258 microM O2, pH 7.5 and 25 degrees C.

Topics: Anaerobiosis; Animals; Cattle; Electron Spin Resonance Spectroscopy; Electron Transport; Free Radicals; Fumarates; Hydrogen-Ion Concentration; Kinetics; Mitochondria; Mitochondria, Heart; Models, Biological; NADP; NADPH-Ferrihemoprotein Reductase; Oxidation-Reduction; Oxygen Consumption; Potassium Cyanide; Submitochondrial Particles; Succinates; Succinic Acid; Superoxide Dismutase; Superoxides; Ubiquinone; Vitamin K