On the origin, evolution, and nature of programmed cell death: a timeline of four billion years

Abstract

Programmed cell death is a genetically regulated process of cell suicide that is central to the development, homeostasis and integrity of multicellular organisms. Conversely, the dysregulation of mechanisms controlling cell suicide plays a role in the pathogenesis of a wide range of diseases. While great progress has been achieved in the unveiling of the molecular mechanisms of programmed cell death, a new level of complexity, with important therapeutic implications, has begun to emerge, suggesting (i) that several different selfdestruction pathways may exist and operate in parallel in our cells, and (ii) that molecular effectors of cell suicide may also perform other functions unrelated to cell death induction and crucial to cell survival. In this review, I will argue that this new level of complexity, implying that there may be no such thing as a`bona fide' genetic death program in our cells, might be better understood when considered in an evolutionary context. And a new view of the regulated cell suicide pathways emerges when one attempts to ask the question of when and how they may have become selected during evolution, at the level of ancestral single-celled organisms.

Classification of cell death: recommendations of the Nomenclature Committee on Cell Death

“…As an example, it appears counterintuitive that some cells exert essential functions when they are 'dead' (such as erythrocytes and keratinocytes), and this underscores the importance of clearly defining what is referred to as 'cell death' as well as the multiple processes leading to it. Knowing that the meaning of scientific words changes when knowledge advances and that words, especially when they express changing concepts, [1][2][3][4] can increase confusion, one may adopt one of two opposing views. A significant fraction of the community of cell death researchers refutes nomenclature as an intellectual cage and as forever 'premature', remembering that many investigators desperately searched for 'DNA ladders' during the 1980s and 1990s.…”

Mitochondrial factors with dual roles in death and survival

“…But programmed cell death was generally considered unnecessary for single-cell organisms that do not form multicellular structures such as pseudohyphae of fungi or the seven 'cell-type' structures of sponges (Ameisen, 2002). Nevertheless, it is possible that programmed cell death has an ancient origin to provide single-cell organisms with stress responses to nutrient deprivation and to guard against the spread of pathogens within a colony/species, and that these mechanisms were subsequently adapted to sculpt and maintain multicellular organisms and to prevent tumorigenesis.…”

“…Did cell death originate because it was the method of choice for an intracellular bacterium to escape the eukaryotic cell? Perhaps it evolved to promote survival of single-cell species through selective pressures involving a long disputed evolutionary hypothesis called 'group selection', or these death-promoting properties of mitochondria were harnessed at some later time for the purpose of sculpting complex multicellular structures (Blackstone and Green, 1999;Ameisen, 2002;Borrello, 2005).…”

Redundant cell death mechanisms as relics and backups

“…We hypothesize that an ancestral cell death mechanism was overlayered with added mechanisms. A popular, plausible 46 yet speculative 47 scenario states that the ancestral cell death mechanism (which may have resembled 'necrosis') might stem from the intrusion of the bacterial precursor of the mitochondrion (the endosymbiont) into the precursor of the eukaryotic cell. In favor of the mitochondrial involvement in the emergence of cell death, it appears that some of the mitochondrial proteins which can be involved in mammalian cell death (such as AIF, cytochrome c, and the serine protease HtrA2/Omi) and in yeast cell death (AIF1) 48 are present in the genome of bacterial ancestors of mitochondria, 46,49 as are the evolutionary ancestors of caspases, the meta-caspases.…”