Formation of Palmitic Acid/Ca²⁺Complexes in the Mitochondrial Membrane: A Possible Role in the Cyclosporin-Insensitive Permeability Transition

Abstract

A possible role of palmitic acid/Ca2+ (PA/Ca2+) complexes in the cyclosporin-insensitive permeability transition in mitochondria has been studied. It has been shown that in the presence of Ca2+, PA induces a swelling of mitochondria, which is not inhibited by cyclosporin A. The swelling is accompanied by a drop in membrane potential, which cannot be explained only by a work of the Ca2+ uniporter. With time, the potential is restored. Evidence has been obtained indicating that the specific content of mitochondrial lipids would favor the PA/Ca2+ -induced permeabilization of the membrane. In experiments with liposomes, the PA/Ca2+ -induced membrane permeabilization was larger for liposomes formed from the mitochondrial lipids, as compared to the azolectin liposomes. Additionally, it has been found that in mitochondria of the TNF (tumor necrosis factor)-sensitive cells (WEHI-164 line), the content of PA is larger than in mitochondria of the TNF-insensitive cells (C6 line), with this difference being mainly provided by PA incorporated in phosphatidylethanolamine and especially, cardiolipin. The PA/Ca2+ -dependent mechanism of permeability transition in mitochondria might be related to some pathologies, e.g. myocardial ischemia. The heaviness of myocardial infarction of ischemic patients has been demonstrated to correlate directly with the content of PA in the human blood serum.

Possible Mechanism for Formation and Regulation of the Palmitate-Induced Cyclosporin A-Insensitive Mitochondrial Pore

“…On the other hand, in the absence of P i and other triggers of the Ca 2+ dependent pore, palmitic acid (and other long chain saturated fatty acids) were recently found to induce opening of a pore insensitive to CsA [13 15]. And we have shown that this is accompanied by recovery of ∆ψ on the inner mitochondrial membrane practically to the ini tial level [15]. Thus, the palmitate induced pore is short living and can close spontaneously [13].…”

Effect of surface-potential modulators on the opening of lipid pores in liposomal and mitochondrial inner membranes induced by palmitate and calcium ions

“…It is known that lipid pores can heal spontaneously [46]. Earlier, we showed that in sucrose/mannitol medium, formation of palmitate/Ca 2+ -induced pores in mitochondria was accompanied by a drop in membrane potential followed by gradual recovery to nearly the initial level [7]. However, mitochondria did not restore their volume, which would require removal of impermeant osmotic agents (sucrose and mannitol) from the mitochondrial matrix.…”

“…Fatty acids are substrates for mitochondrial respiration, uncouplers of oxidative phosphorylation, inducers of the mitochondrial permeability transition (MPT) pore and pro-apoptotic agents [1–5]. In the presence of Ca 2+ , long-chain saturated fatty acids also open a cyclosporin A (CsA)-insensitive pore in the mitochondrial inner membrane [6, 7]. Palmitate/Ca 2+ also induces pores in erythrocyte membranes, artificial lipid vesicles, and black lipid membranes [7–11].…”

“…In the presence of Ca 2+ , long-chain saturated fatty acids also open a cyclosporin A (CsA)-insensitive pore in the mitochondrial inner membrane [6, 7]. Palmitate/Ca 2+ also induces pores in erythrocyte membranes, artificial lipid vesicles, and black lipid membranes [7–11]. These findings indicate that the fatty acid/Ca 2+ -induced pore is lipid in nature.…”

Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies

“…Long-chain fatty acids that are routinely present in plasma of normal individuals were shown to have cytotoxic effects at high concentrations, impair ATP generation, uncouple OXPHOS, inhibit the respiratory chain, depolarize mitochondria by their protonophoric properties, induce oxidative stress, and have permeability transition. [44][45][46][47][48][49] Medium-chain fatty acid effects on mitochondrial functions are less studied, but may similarly affect mitochondrial respiration and disturb the translocation of ADP in mitochondria. 50 Therefore, it is feasible that the fatty acids that accumulate in tissues of patients with MCAD and LCHAD deficiencies (Table 3) may similarly induce cellular toxicity.…”