Free fatty acid effects on mitochondrial permeability: An overview

A variety of experimental conditions elicit increases in mitochondrial perm eability that can be differentiated from the classic cyclosporin A (CsA)-se nsitive mitochondrial permeability transition (MPT). For example, butylated hydroxytoluene, signal peptides, and the hormone thyroxine have been shown to promote increases in mitochondrial permeability that are CsA-insensitiv e. Our laboratory has recently demonstrated that palmitic acid, a saturated Is-carbon free fatty acid (FFA), can also open a CsA-insensitive pore. Thi s nonclassic permeability transition (NCPT) is further distinguished by a n onselective dependence on divalent cations and by spontaneous closure. To d etermine if induction of the NCPT is specific to palmitic acid and to resol ve conflicting reports as to the mechanisms by which FFAs alter mitochondri al permeability, we examined in detail mitochondrial swelling induced by FF As that differ in chain length and degree of saturation. The following resu lts were obtained: (1) In the presence of modest Ca2+ concentrations (75 nm ol/mg protein), medium-chain FFAs (C12-C18) were more effective in elicitin g mitochondrial swelling than were shorter or longer FFAs; medium-chain alk anols and amines had no effect. (2) Under these conditions, saturated FFAs induced CsA-insensitive swelling with all the characteristics of the NCPT, while unsaturated FFAs triggered the MPT, (3) When matrix Ca2+ concentratio n was further elevated, unsaturated FFAs, triggered the NCPT. (4) Mitochond rial swelling induced by saturated FFAs was inhibited by unsaturated FFAs b ut not by other saturated FFAs or medium-chain alkanols, These results sugg est that ambient conditions can greatly influence the nature of the increas e in mitochondrial permeability induced by FFAs, They are also consistent w ith our earlier proposal that Ca2+ (Or Sr2+) binding to FFAs in the inner l eaflet of the inner mitochondrial membrane underlies the NCPT. (C) 2001 Aca demic Press.