Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes

Abstract

Apoptotic cell death is a type of eukaryotic cell death. In animals, it regulates development, is involved in cancer suppression, and causes cell death during pathological aging of neuronal cells in neurodegenerative diseases such as Alzheimer’s. Mitochondrial apoptotic-like cell death, a form of primordial apoptosis, also occurs in unicellular organisms. Here, we ask the question why the apoptosis machinery has been acquired and maintained in unicellular organisms and attempt to answer it by performing ancestral state reconstruction. We found indications of an ancient evolutionary arms race between protomitochondria and host cells, leading to the establishment of the currently existing apoptotic pathways. According to this reconstruction, the ancestral protomitochondrial apoptosis machinery contained both caspases and metacaspases, four types of apoptosis induction factors (AIFs), both fungal and animal OMI/HTR proteases, and various apoptotic DNases. This leads to the prediction that in extant unicellular eukaryotes, the apoptotic factors are involved in mitochondrial respiration and their activity is needed exclusively in aerobic conditions. We test this prediction experimentally using yeast and find that a loss of the main apoptotic factors is beneficial under anaerobic conditions yet deleterious under aerobic conditions in the absence of lethal stimuli. We also point out potential medical implications of these findings.

The Nature of Programmed Cell Death

“…The evolution of PCD has been tackled from several angles (Ameisen, 2002, Bayles, 2014, Bidle, 2016, Franklin et al, 2006, Kaczanowski et al, 2011, Koonin and Aravind, 2002, Lewis, 2000, Nedelcu et al, 2011, Pepper et al, 2013, Iranzo et al, 2014, Klim et al, 2018 although an explicit evolutionary definition is seldom provided. However, we claim that it is the evolutionary history that bears on whether something should be considered true PCD or not.…”

“…Until now, there has been considerable discussion of how PCD may evolve, both by nonadaptive pleiotropic means (for example Frade and Michaelidis, 1997), and by natural selection (for example van Zandbergen et al, 2010). However, the extensive discussions of the evolution of PCD (Ameisen, 2002, Nedelcu et al, 2011, Pepper et al, 2013, Ramisetty et al, 2015, Berges and Choi, 2014, Gardner and Kummerli, 2008, Klim et al, 2018, Koonin and Aravind, 2002 have not always clearly articulated the distinction between these questions, and have not offered a definition of PCD that allows for PCD to be defined independently of the mechanisms that realize it.…”

“…Should we consider it an adaptation? This debate has been ongoing ever since PCD was found to occur in unicellular organisms (for the latest see Klim et al, 2018).…”

“…Such explanations are generally framed in terms of fitness costs and benefits to individuals, their kin, or groups of conspecifics (Ameisen, 2002, Bayles, 2014, Nedelcu et al, 2011, Pepper et al, 2013. PCD has also been considered in broader ecological contexts like phytoplankton ecology (Franklin et al, 2006, Berges and Choi, 2014, Bidle, 2015, the microbial loop (Bidle, 2016, Orellana et al, 2013, microalgal blooms (Vardi et al, 2007), conflict mediation in group formation and evolutionary transitions (Fisher et al, 2013, Hanschen et al, 2018, Kapsetaki et al, 2017, Michod, 2003, Michod and Roze, 2001, Sathe and Durand, 2016, propagule formation in the experimental evolution of multicellularity (Ratcliff et al, 2012), the evolution of different kinds of complexity (Durand et al, 2016), the evolution of aerobic metabolism and the eukaryote cell (Klim et al, 2018, Kaczanowski et al, 2011, Koonin and Aravind, 2002, and as a virus-host arms race (Iranzo et al, 2014).…”

Enhancing the promiscuity of a member of the Caspase protease family by rational design

“…Twelve different members of the Caspase family have been described in humans 31,32 . Caspases are abundant in all animals and are even related to plant and fungal analogous proteases called metacaspases 33 …”