Scheme 1. Quinone-mediated mitochondrial electron transport complex I bypass.

A. The mitochondrial electron transport chain under physiological conditions, where C(I), C(III), C(IV) and C(V) represent complexes I, III, IV and V, and with the physiological quinone electron acceptor, CoQ₁₀, and its reduced form, CoQ₁₀H₂. B. Rotenone inhibits electron transport at C(1), blocking transfer of electron to CoQ₁₀ and thus to C(III), preventing generation of the proton gradient across the mitochondrial inner membrane, depolarizing the mitochondrial membrane potential (ΔΨ_m) and depressing ATP production. Compensatory activation of glycolysis increases lung lactate generation as a reflection of increased cytosolic NADH levels. C. When the exogenous amphipathic quinone (Q₁) is present, it freely enters the lung tissue, where it is reduced via cytosolic NQO1 at the expense of the endogenous electron donor, NAD(P)H. The reduced hydroquinone form, Q₁H₂, enters the mitochondria and transfers the reducing equivalents gained in the cytosol to C(III), thereby restoring mitochondrial electron transport, proton pumping, ΔΨ_m and ATP generation. The reoxidized quinone (Q₁) returns to the cytosol to repeat the cycle. Thus, the Q₁-Q₁H₂ redox pair acts to shuttle electrons from cytosolic NAD(P)H to C(III).