Abstract

It is known that activated derivatives of long-chain fatty acids acylcarnitines (LCAC) are considered the most toxic, which, along with calcium, can participate in the induction of the mitochondrial pore, involving various types of phospholipases. In this study, the effect of inhibitors of Ca²⁺-independent and Ca²⁺-dependent phospholipases, as well as an inhibitor of carnitine palmitoyltransferase on the induction of pores with D,L-palmitoylcarnitine (PC, C16:0) was investigated. In experiments on isolated rat liver mitochondria, the effect of PC on mitochondrial respiration rate, membrane potential (ΔΨm) and mitochondrial swelling during oxidation of glutamate and pyruvate or succinate was studied. It was shown that inhibitors of carnitine palmitoyltransferase-1 etomoxir 2, Ca²⁺-dependent phospholipase cPLA2 aristolochic acid or Ca²⁺-independent phospholipase iPLA2γ bromoenol lactone and PACOCF3 caused an increase in critical concentrations of D,L-palmitoylcarnitine (PC*), which were required to decrease the membrane potential and induce mitochondrial swelling. In the ADP activated state 3 (ADP + Mg²⁺ + hexokinase), Ethomoxir 2 and aristolochic acid promoted the inhibition of respiration and dissipation of membrane potential caused by excess of PC, while phospholipase inhibitors iPLA2γ PACOCF3 and bromoenol lactone provided a pronounced protective effect. Inhibition of iPLA2γ prevented the decrease of ΔΨm and inhibition of respiration caused by PC. Thus, the results obtained indicated the involvement of mitochondrial phospholipase iPLA2γ in the induction of the mitochondrial pore by long-chain acylcarnitines.

中文翻译：

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线粒体 Ca2+ 独立磷脂酶 iPLA2 参与长链酰基肉碱诱导线粒体通透性转变孔

摘要

众所周知，长链脂肪酸酰基肉碱（LCAC）的活化衍生物被认为是毒性最大的，它与钙一起可以参与线粒体孔的诱导，涉及各种类型的磷脂酶。在本研究中，研究了Ca ²⁺非依赖性和 Ca ²⁺依赖性磷脂酶抑制剂以及肉碱棕榈酰转移酶抑制剂对D , L -棕榈酰肉碱 (PC, C16:0) 诱导孔的影响。在离体大鼠肝线粒体实验中，研究了 PC 对谷氨酸、丙酮酸或琥珀酸氧化过程中线粒体呼吸速率、膜电位 (ΔΨm) 和线粒体肿胀的影响。结果表明，肉毒碱棕榈酰转移酶 1 依托莫克西 2、Ca ²⁺依赖性磷脂酶 cPLA2 马兜铃酸或 Ca ^{2+非依赖性磷脂酶 iPLA2γ 溴烯醇内酯和 PACOCF3 抑制剂导致}D , L -棕榈酰肉碱 (PC*)临界浓度增加，这是降低膜电位并诱导线粒体肿胀所必需的。在ADP激活状态3（ADP + Mg ²⁺ +己糖激酶）下，乙莫克西2和马兜铃酸促进了过量PC引起的呼吸抑制和膜电位耗散，而磷脂酶抑制剂iPLA2γ PACOCF3和溴烯醇内酯提供了明显的保护作用。抑制 iPLA2γ 可防止 PC 引起的 ΔΨm 减少和呼吸抑制。因此，获得的结果表明线粒体磷脂酶 iPLA2γ 参与长链酰基肉碱诱导线粒体孔。