Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids

https://doi.org/10.1016/j.bbrc.2016.11.005Get rights and content

Highlights

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    Phospholipid (PL) signaling in elimination of organelles and cells is reviewed.

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    Anionic PL membrane asymmetry generates distinct signals for elimination.

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    Oxidation of cardiolipin is a required stage in mitochondrial apoptosis.

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    Oxidation of externalized phosphatidylserine enhances phagocytosis efficiency.

Abstract

High fidelity of biological systems is frequently achieved by duplication of the essential intracellular machineries or, removal of the entire cell, which becomes unnecessary or even harmful in altered physiological environments. Carefully controlled removal of these cells, without damaging normal cells, requires precise signaling, and is critical to maintaining homeostasis. This review describes how two anionic phospholipids - phosphatidylserine (PS) and cardiolipin (CL) - residing in distinct compartments of the cell, signal removal of “the unnecessary” using several uniform principles. One of these principles is realized by collapse of inherent transmembrane asymmetry and the externalization of the signal on the outer membrane surface - mitochondria for CL and the plasma membrane for PS – to trigger mitophagy and phagocytosis, respectively. Release from damaged cells of intracellular structures with externalized CL or externalized PS triggers their elimination by phagocytosis. Another of these principles is realized by oxidation of polyunsaturated species of CL and PS. Highly specific oxidation of CL by cytochrome c serves as a signal for mitochondria-dependent apoptosis, while oxidation of externalized PS improves its effectiveness to trigger phagocytosis of effete cells.

Introduction

The subject of “the unnecessary” has been metaphorically and also constructively discussed and used by artists, politicians, and economists with different goals and in different contexts. Perhaps one of the most illuminating examples of this is a well-known principle in Pablo Picasso's creative life namely that “art is the elimination of the unnecessary”, which he so exquisitely and skillfully applied to his work. We ask, what may be the relevance of this principle to biological processes?

The reliability of biological processes is achieved, to a large extent, through the initial generation of excessive amounts of biological material, including organelles and cells, which upon successful completion of their specific functions become unnecessary. Removal of the unnecessary in a timely manner is essential to prevent the unnecessary from becoming undesired or even harmful. This principle is well illustrated during development, such as in the elimination of the tail in the tadpole during metamorphosis [1] and tissue remodeling of a vertebrate limb bud during development [2], wherein unnecessary cells and tissue are removed through the process of apoptosis. Elimination of unnecessary cells also occurs in inflammation, wherein specialized cells recruited to the inflammation site must be cleared after successful completion of their job. Other examples include, mammary gland involution and ovarian follicle atresia, which are characterized by removal of milk-producing epithelial cells [3] and immature ovarian follicles [4] respectively, through apoptosis. The importance of clearance is underscored by observations that its inhibition results in severe developmental defects, organismal lethality [5], [6], [7], autoimmune disease [8], [9], or promotion of tumorigenesis [10]. Thus, robust and reliable mechanisms that direct timely removal of unwanted cells are essential, not just for maintenance of homeostasis, but also for circumventing undesired pathophysiological consequences. Given the remarkable importance of eliminating of the unnecessary in biology, in this brief review, we will consider recent advancements in our understanding of the role that two anionic phospholipids – phosphatidylserine (PS) and cardiolipin (CL) – play in the signaling and clearance of “unnecessary” organelles and cells.

Section snippets

Synthesis and localization of PS and CL

There are at least two different ways in which PS and CL participate in different types of elimination signaling: a) by trans-membrane re-distribution and subsequent appearance on the cell/organelle surfaces thus enabling recognition by specialized receptors and b) by oxidation of polyunsaturated acyl chains of the phospholipid molecules leading to modification of the membranes including their barrier functions. Intriguingly, PS and CL are compartmentalized in cells such that CL is localized

PS externalization is an engulfment signal

When phagocytosis was first discovered and described by I. Mechnikov in 1883 [44], the molecular dynamics of signaling and the role of PS externalization was unknown. It took more than a century that witnessed a multitude of fundamental discoveries in biology before it was established that one of the hallmarks of the activation of apoptosis and initiation of phagocytosis is the appearance of PS on the outer leaflet of the apoptotic cell membrane [45], [46]. The externalized PS is a recognition

PS oxidation promotes apoptotic cell clearance

During inflammation, massive production of reactive oxygen species (ROS) creates pro-oxidant environments potentially favoring PS oxidation [61], yet for phagocytosis, externalized PS is not required to be oxidized. However, presenting externalized, oxidized PS strongly enhances the effectiveness of phagocytosis [62]. Cells grown in cultures on standard media do not contain significant amounts of oxidizable PS, yet apoptosis and macrophage phagocytosis can be triggered. Metabolic incorporation

CL asymmetry is a signal for mitophagy

From a signaling perspective, externalization of PS on the cell membrane, is similar to CL externalization on the mitochondrial surface (Fig. 1). Factors that determine the need for mitophagy may include maintenance of an adequate membrane potential, oxidation of proteins and lipids and the ability of mitochondria to undergo biogenesis. Mitochondrial externalization of CL serves as an elimination sign initiating mitophagy in analogy to PS externalization which signals phagocytosis, yet the

CL oxidation elicits intrinsic apoptosis

While mitophagy is a pro-survival rescue pathway, the continued accumulation of mitochondrial impairments and the insufficiency and/or failure of repair mechanisms may necessitate the elimination of the entire cell through the activation of the apoptotic program. This requires not only the presence of externalized CL, but also oxidation of its polyunsaturated acyl chain(s). Historically, the involvement of CLs in (BAX-mediated) apoptosis had been proposed and supported by the work of Kuwana

Phagocytosis of extracellular mitochondria

When an effective biological solution evolves, it is frequently adapted and widely used. Autophagy of mitochondria and phagocytic removal of cells both depend on similar signaling systems although the processes are quite different. Interestingly, recent studies demonstrated that macrophages have evolved to retain mechanisms to target CLs on extracellular mitochondria for phagocytosis [105]. While the details and machinery of eliminating extracellular mitochondria remain a subject of interest,

Concluding remarks

Reliability in biology frequently requires an excess of constituents including metabolites, enzymes, organelles, and cells. During times of change and stress, such as growth, injury, or infection, this excess can become unnecessary and detrimental. Elimination of the unnecessary applies to many facets of biology. Here we described how PS and CL, two distinct phospholipids, have evolved to signal transformative yet similar cellular processes that eliminate “the unnecessary”. Discerning this

Acknowledgements

The authors are supported, in part, by NIH: PO1HL114453, CA165065, ES020693, U19AIO68021, NS076511, NS061817; NIOSH: OH008282, Human Frontier Science Program HFSP-RGP00132014, the Barth Syndrome Foundation and the Barth Syndrome Foundation of Canada and the Swedish Research Council (BF).

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