A lipid perspective on regulated cell death

Abstract

Lipids are fundamental to life as structural components of cellular membranes and for signaling. They are also key regulators of different cellular processes such as cell division, proliferation, and death. Regulated cell death (RCD) requires the engagement of lipids and lipid metabolism for the initiation and execution of its killing machinery. The permeabilization of lipid membranes is a hallmark of RCD that involves, for each kind of cell death, a unique lipid profile. While the permeabilization of the mitochondrial outer membrane allows the release of apoptotic factors to the cytosol during apoptosis, permeabilization of the plasma membrane facilitates the release of intracellular content in other nonapoptotic types of RCD like necroptosis and ferroptosis. Lipids and lipid membranes are important accessory molecules required for the activation of protein executors of cell death such as BAX in apoptosis and MLKL in necroptosis. Peroxidation of membrane phospholipids and the subsequent membrane destabilization is a prerequisite to ferroptosis. Here, we discuss how lipids are essential players in apoptosis, the most common form of RCD, and also their role in necroptosis and ferroptosis. Altogether, we aim to highlight the contribution of lipids and membrane dynamics in cell death regulation.

Introduction

Regulated cell death (RCD) is fundamental for the development and tissue homeostasis of multicellular organisms. It can be triggered under several physiological conditions and the imbalance between cell death and proliferation has been linked to many diseases, including autoimmunity, viral infections, neurodegenerative diseases and cancer (Nagata and Tanaka, 2017). Given the relevance of RCD to different human pathologies, its mechanisms of action and modulation by small molecules, is of profound therapeutic interest. Apoptosis constitutes the most frequent form of RCD in vertebrates. Well-defined morphological features are linked with apoptotic cell death, such as membrane blebbing, pyknotic nuclei formation, phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane, etc. A variety of additional nonapoptotic forms of RCD have recently been described, including necroptosis and ferroptosis, amongst others. These forms of RCD involve disruption of the plasma membrane (PM), cellular swelling and release of damage-associated molecular patterns (DAMPs), and have an inflammatory phenotype (Linkermann et al., 2013; Vince and Silke, 2016; Wallach et al., 2016; Zhang et al., 2018). While membrane permeabilization appears as common theme in RCD, each form of cell death involves unique membrane-related changes that trigger and regulate their distinct biochemical machinery (Zhang et al., 2018). This is not surprising considering that lipids are essential structural biomolecules that are important for signaling in cell death (Friedmann Angeli et al., 2019; Phan et al., 2019; Tonnus et al., 2019).

Lipids have a key role as structural components in the membrane, where cell death-inducing proteins elicit pore formation. Each lipid species has a concrete form and shape, built by a defined combination of core structures, head groups and acyl chains. The unique physiochemical properties of specific lipids do not only modulate their location and the properties of membranes where they are integrated, but also their interactions with different mediators of RCD (Agmon and Stockwell, 2017; Bleicken et al., 2017; Flores-Romero et al., 2018; Magtanong et al., 2016). Lipids can enhance cell death by, for example, modulating the affinities between molecular executors and regulators (Kuwana et al., 2002). Indeed, in apoptosis, lipids constitute the building blocks of the proteolipidic apoptotic pore (Gonzalvez et al., 2005, Gonzalvez et al., 2008; Jalmar et al., 2013). Moreover, membrane lipids play an important role in membrane dynamics during RCD (Cosentino and Garcia-Saez, 2014; Ugarte-Uribe and Garcia-Saez, 2017). However, despite intense research efforts to study lipids at the molecular level, the functions of individual lipids in many cellular processes, including cell death, remain poorly defined. Here, we discuss current knowledge about the role of different lipids in apoptosis and two of the best-characterized forms of RCD, necroptosis and ferroptosis.