Based on our recent findings concerning the generating, partitioning, targeting, and functioningof superoxide in mitochondria, a hypothetical model involving a “reactive oxygen cycle” inthe respiratory chain has been proposed (Liu and Huang, 1991, 1996; Liu et al., 1996; Liu,1997, 1998) This model emphasizes that during State 4 respiration, an interaction between anelectron leak (a branch of electron transfer directly from the respiratory chain to form O^•- ₂,but not H₂O) and a proton leak (a branch pathway which utilizes to produce heat, butnot ATP) may take place in cooperation with the Q and proton cycles in mitochondria throughthe consumption of H⁺ by O^•- ₂ anions to form a protonated perhydroxyl radical, HO₂, whichis directly permeable across the inner mitochondrial membrane and induces proton leakageand a decrease of . O^•- ₂ generation in the mitochondrial respiratory chain and its cyclingacross the inner membrane may have the role of an endogenous protonophore in regulating andpartitioning energy transduction and heat production, as well as in pathogenesis of mitochondrialdiseases, aging, and apoptosis. The present article summarizes the supporting experimentalevidence obtained in this laboratory and presents a brief description of the theoretical basisof this model