The stimulation of succinate-fueled respiration of rat liver mitochondria in state 4 by α,ω-hexadecanedioic acid without induction of proton conductivity of the inner membrane. Intrinsic uncoupling of the bc complex.

The paper shows that natural α,ω-dioic acid, α,ω-hexadecanedioic acid (HDA), is able to stimulate the respiration of succinate-fueled rat liver mitochondria in state 4 without induction of proton conductivity of the inner membrane. This effect of HDA is less pronounced in glutamate/malate-fueled mitochondria, as well as in the case of ascorbate/TMPD or ascorbate/ferrocyanide substrate systems, which transfer electrons directly to cytochrome c. It is noted that HDA-induced stimulation of respiration is not associated with damage to the inner membrane in a part of mitochondria and with shunting of electrons through the bc complex. Therefore, HDA can be considered as a natural decoupling agent. Specific inhibitors of the bc complex (antimycin A and myxothiazole) as well as malonate and dithionitrobenzoate were used in the inhibitory analysis. These and other experiments have shown that during the oxidation of succinate in liver mitochondria, the decoupling effect of HDA is mainly carried out at the level of the bc complex. We hypothesized that HDA is capable of promoting the cyclic transport of protons within the bc complex and thus switch this complex to the idle mode of operation (intrinsic uncoupling of the bc complex). Induction of free respiration in liver mitochondria by HDA at the level of the bc complex is considered as one of the "rescue pathways" of hepatocytes in various pathological conditions, accompanied by disorders of carbohydrate and lipid metabolism and increased oxidative stress.