Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, United States.
World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, Russia.
Front Endocrinol (Lausanne). 2021 Feb 19;11:628079. doi: 10.3389/fendo.2020.628079. eCollection 2020.
A huge diversification of phospholipids, forming the aqueous interfaces of all biomembranes, cannot be accommodated within a simple concept of their role as membrane building blocks. Indeed, a number of signaling functions of (phospho)lipid molecules has been discovered. Among these signaling lipids, a particular group of oxygenated polyunsaturated fatty acids (PUFA), so called lipid mediators, has been thoroughly investigated over several decades. This group includes oxygenated octadecanoids, eicosanoids, and docosanoids and includes several hundreds of individual species. Oxygenation of PUFA can occur when they are esterified into major classes of phospholipids. Initially, these events have been associated with non-specific oxidative injury of biomembranes. An alternative concept is that these post-synthetically oxidatively modified phospholipids and their adducts with proteins are a part of a redox epiphospholipidome that represents a rich and versatile language for intra- and inter-cellular communications. The redox epiphospholipidome may include hundreds of thousands of individual molecular species acting as meaningful biological signals. This review describes the signaling role of oxygenated phospholipids in programs of regulated cell death. Although phospholipid peroxidation has been associated with almost all known cell death programs, we chose to discuss enzymatic pathways activated during apoptosis and ferroptosis and leading to peroxidation of two phospholipid classes, cardiolipins (CLs) and phosphatidylethanolamines (PEs). This is based on the available LC-MS identification and quantitative information on the respective peroxidation products of CLs and PEs. We focused on molecular mechanisms through which two proteins, a mitochondrial hemoprotein cytochrome (cyt ), and non-heme Fe lipoxygenase (LOX), change their catalytic properties to fulfill new functions of generating oxygenated CL and PE species. Given the high selectivity and specificity of CL and PE peroxidation we argue that enzymatic reactions catalyzed by cyt /CL complexes and 15-lipoxygenase/phosphatidylethanolamine binding protein 1 (15LOX/PEBP1) complexes dominate, at least during the initiation stage of peroxidation, in apoptosis and ferroptosis. We contrast cell-autonomous nature of CLox signaling in apoptosis correlating with its anti-inflammatory functions non-cell-autonomous ferroptotic signaling facilitating pro-inflammatory (necro-inflammatory) responses. Finally, we propose that small molecule mechanism-based regulators of enzymatic phospholipid peroxidation may lead to highly specific anti-apoptotic and anti-ferroptotic therapeutic modalities.
磷脂种类繁多，构成了所有生物膜的水相界面，其功能不能仅用简单的“构成膜的结构单元”来解释。事实上，人们已经发现了一些（磷酸）脂分子的信号功能。在这些信号脂质中，一组特定的含氧多不饱和脂肪酸（PUFA），即所谓的脂质介质，经过几十年的深入研究。这一组包括含氧十八碳烷酸、二十碳烷酸和二十二碳烷酸，包括数百种不同的物质。PUFA 酯化形成主要的磷脂类时，就会发生氧化。最初，这些事件与生物膜的非特异性氧化损伤有关。另一种观点是，这些经过合成后氧化修饰的磷脂及其与蛋白质的加合物是氧化还原类脂磷信使组的一部分，这是细胞内和细胞间通讯的一种丰富而多样的语言。氧化还原类脂磷信使组可能包含数十万种作为有意义的生物学信号的单个分子。本综述描述了含氧磷脂在调控细胞死亡程序中的信号作用。尽管磷脂过氧化与几乎所有已知的细胞死亡程序都有关联，但我们选择讨论在细胞凋亡和铁死亡中激活的酶促途径，并导致两种磷脂类（心磷脂（CL）和磷脂酰乙醇胺（PE））的过氧化。这是基于对 CL 和 PE 各自过氧化产物的 LC-MS 鉴定和定量信息。我们专注于两种蛋白质（一种线粒体血红素蛋白细胞色素（cyt）和非血红素铁加氧酶（LOX））通过改变其催化特性来发挥产生含氧 CL 和 PE 物质的新功能的分子机制。鉴于 CL 和 PE 过氧化的高选择性和特异性，我们认为至少在细胞凋亡和铁死亡的起始阶段，由 cyt/CL 复合物和 15-LOX/PEBP1 复合物催化的酶促反应占主导地位。我们将细胞凋亡中 CLox 信号的自主性质与抗炎功能进行对比，而非细胞自主的铁死亡信号促进促炎（坏死性炎症）反应。最后，我们提出基于小分子的酶促磷脂过氧化的机制调节剂可能导致高度特异的抗凋亡和抗铁死亡治疗方式。
