Potential mechanisms for mSOF generation. (A) Mechanism 1: Pore opening triggers mSOF events. A small increase in constitutive ROS production opens a large pore channel to cause depolarization of the mitochondrial membrane potential, which subsequently stimulates the ETC to produce a burst in superoxide production. (B) Mechanism 2: Pore opening terminates mSOF events. A mild hyperpolarization of the mitochondrial inner membrane potential results in a dramatic increase in superoxide production from complex I, which triggers the opening of a large pore channel that depolarizes the mitochondrial membrane potential. The pore opening dissipates the electrical and proton gradient across the inner membrane to terminate ETC-dependent superoxide production from complex I (see text for details). ETC, electron transport chain; ETF-QO, electron transferring flavoprotein-quinone oxidoreductase; ANT, adenine nucleotide translocase; mPTP, mitochondrial permeability transition pore; Cyt C, cytochrome C; Q, Q cycle; Cx I, II, III, IV, complex I, II, III, IV; TMRE, tetramethylrhodamine ethyl ester. Red “explosion” symbols indicate places where electron leak and superoxide production occur. Green arrows indicate stimulatory effects, and red arrows indicate inhibitory effects.