Mitochondria and endomembrane origins
2018; Elsevier BV; Volume: 28; Issue: 8 Linguagem: Inglês
10.1016/j.cub.2018.03.052
ISSN1879-0445
Autores Tópico(s)Genomics and Phylogenetic Studies
ResumoFor this series of articles on the topic of Membranes, it is perhaps appropriate to begin by considering where these membranes came from in the first place. By envisioning the origins of cellular compartmentalization, we can better understand the intrinsic motivations that drive cell biological events today. This editorial for the series will speculate upon recent ideas in evolutionary theory, with a focus on the contribution of mitochondria as a driving force in the emergence of the endomembrane system within the earliest eukaryotic cell. The collection of Reviews, Primers and Quick guides will expand on a host of exciting topics, from the ciliary membrane to membrane repair, membrane trafficking in cytokinesis, tethering complexes, SNAREs, and much more, including a more detailed overview of the evolutionary origin of intracellular membranes by Sven Gould. But, for now, we will imagine the very origin of the membrane systems that we know today. It is widely accepted that the eukaryotic cell evolved from the capture of ancestral mitochondria, or alphaproteobacteria, within primitive archaea around 2 billion years ago [1Gould S.B. Garg S.G. Martin W.F. Bacterial vesicle secretion and the evolutionary origin of the eukaryotic endomembrane system.Trends Microbiol. 2016; 24: 525-534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. This remarkable event cemented mitochondria as an organelle within a eukaryotic cell, and set in motion an evolving symbiotic relationship between the captured bacterium and its archaeal host. An exciting recent advance was the identification of a proposed new lineage of archaea called Lokiarchaeota (or Loki). Their genomes were assembled from metagenome data that were assembled from samples collected at a hydrothermal vent field in the Arctic ocean, called ‘Loki’s castle’ [2Spang A. Saw J.H. Jorgensen S.L. Zaremba-Niedzwiedzka K. Martijn J. Lind A.E. van Eijk R. Schleper C. Guy L. Ettema T.J.G. Complex archaea that bridge the gap between prokaryotes and eukaryotes.Nature. 2015; 521: 173-179Crossref PubMed Scopus (700) Google Scholar, 3Zaremba-Niedzwiedzka K. Caceres E.F. Saw J.H. Backstrom D. Juzokaite L. Vancaester E. Seitz K.W. Anantharaman K. Starnawski P. Kjeldsen K.U. et al.Asgard archaea illuminate the origin of eukaryotic cellular complexity.Nature. 2017; 541: 353-358Crossref PubMed Scopus (564) Google Scholar]. Loki is a member of the Asgard archaea superphylum, and phylogenomic analyses suggest they represent the descendants of a lineage that provided the archaeal partner of eukaryogenesis and the ‘transitional organism’ of the last eukaryotic common ancestor. While there is ongoing debate over the origin of membranes within the eukaryotic cell, the acquisition of ancestral mitochondria would have created an urgent evolutionary pressure for the archaea to adapt and accommodate the needs of this new intracellular organelle. Given that mitochondria are autonomous organelles containing their own genomes, the replication and segregation of mitochondrial DNA was certainly a major driving force in shaping the behavior of these organelles within the archaea. Moreover, the newly intracellular alphaproteobacteria would continue to shed vesicles, forcing the archaea to deal with these new membrane-bound structures [4Kim J.H. Lee J. Park J. Gho Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles.Semin. Cell Dev. Biol. 2015; 40: 97-104Crossref PubMed Scopus (224) Google Scholar]. Similarly, contact sites with either the early plasma membrane or an elaborated endoplasmic reticulum would have been essential in providing lipids and iron to ensure mitochondrial growth. This editorial will explore the evolutionary implications of the early alphaproteobacteria as a driving force in the development of an endomembrane system in eukaryotic cells. In considering the origin of intracellular membranes, traditional views posit that the archaea had previously acquired phagocytic properties in order to engulf the alphaproteobacterial ancestor of mitochondria. Indeed, the recent identification of Loki lent some support for this model, as DNA sequence analysis revealed the presence of what could be considered membrane-related proteins, including small GTPases, proteins related to vesicle coats, a ubiquitin-related system, and cytoskeletal sequences related to actin [3Zaremba-Niedzwiedzka K. Caceres E.F. Saw J.H. Backstrom D. Juzokaite L. Vancaester E. Seitz K.W. Anantharaman K. Starnawski P. Kjeldsen K.U. et al.Asgard archaea illuminate the origin of eukaryotic cellular complexity.Nature. 2017; 541: 353-358Crossref PubMed Scopus (564) Google Scholar]. Unfortunately, the DNA was obtained from environmental sequencing, not from isolated cells, so, while the presence of small GTPases may hint at a pre-existing endomembrane system, this cannot be perceived as a final proof [5Dey G. Thattai M. Baum B. On the archaeal origins of eukaryotes and the challenges of inferring phenotype from genotype.Trends Cell Biol. 2016; 26: 476-485Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. Moreover, no images of Loki have yet been seen, so we cannot directly visualize internal membranes within this new lineage. This is important, since there are currently no known archaea that contain endomembranes, something that would be expected if this ‘intermediate’ in eukaryogenesis had existed. In general, it is difficult to provide evidence for a specific evolutionary driver that would have initiated the process of endocytosis within the ancient Loki family, given the fact that all current archaea manage quite well without it. On the other hand, it is clear that the presence of mitochondria within the archaea would have forced considerable adaptive change in the host to accommodate such a demanding constituent. These pressures have convinced some evolutionary biologists to consider that the acquisition of mitochondria was the major driving force for the development of the entire endomembrane system [1Gould S.B. Garg S.G. Martin W.F. Bacterial vesicle secretion and the evolutionary origin of the eukaryotic endomembrane system.Trends Microbiol. 2016; 24: 525-534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. This ‘mitochondria-first’ model suggests that the alphaproteobacteria may have infected or invaded the phagosome-deficient archaea (Figure 1), a proposal that is certainly consistent with the ability of these bacteria to be invasive. Whichever came first, it is clear that the acquisition of mitochondria initiated the development of entirely new cell biology that was essential for mitochondria to adapt to their new environment. Thinking about the origin of membranes from a mitochondrial perspective provides unique insights into the current level of connections between mitochondria and the endomembrane system in general, changing the common perception of mitochondria as singular, segregated organelles within the eukaryotic cell. One of the first essential processes for the newly acquired mitochondria would have been the ability to replicate within the archaeal host. Bacterial and archaeal cell division is orchestrated by members of the FtsZ family, which oligomerize at the division site [6Xiao J. Goley E.D. Redefining the roles of the FtsZ-ring in bacterial cytokinesis.Curr. Opin. Microbiol. 2016; 34: 90-96Crossref PubMed Scopus (59) Google Scholar]. FtsZ proteins are distant members of the GTP-binding tubulin family, and they require adaptors that mark the site of division. Some archaea also utilize ancestors of components of the endosomal sorting complexes required for transport III (ESCRT-III)/Vps4 machinery to facilitate their division [7Samson R.Y. Obita T. Hodgson B. Shaw M.K. Chong P.L. Williams R.L. Bell S.D. Molecular and structural basis of ESCRT-III recruitment to membranes during archaeal cell division.Mol. Cell. 2011; 41: 186-196Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Most eukaryotic cells, particularly within the metazoan clade, have not retained an obvious FtsZ-type GTPase, and cell division has evolved into a more complex process that remains based upon the original building blocks found within the archaea, including components of ESCRT and tubulin (FtsZ) families. Initially, the alphaproteobacteria would have carried their own internal fission system upon entering the archaea, a system that was lost as the genes were transferred over to the archaeal genome. At some point, cytosolic GTPases called bacterial dynamin-like proteins (BDLP) were then recruited to the mitochondria to drive their division. BDLPs are present in all bacteria and some archaea, so the function of these GTPases at the surface of mitochondria may have emerged after these genes were transferred from the alphaproteobacterial genome to the archaeal genome. So, how, when and why did this family of GTPases begin to act at sites of alphaproteobacterial/mitochondrial division? For this we must consider what the earliest function of these GTPases might have been. While sequences are known and some structures solved, the exact function of BDLPs within current bacteria was not understood until recently. The BDLP DynA from the filamentous soil bacteria Streptomyces venezuelae is not an essential gene, but was shown to stabilize the rings of FtsZ at the septum of sporulating bacteria [8Schlimpert S. Wasserstrom S. Chandra G. Bibb M.J. Findlay K.C. Flardh K. Buttner M.J. Two dynamin-like proteins stabilize FtsZ rings during Streptomyces sporulation.Proc. Natl. Acad. Sci. USA. 2017; 114: E6176-E6183Crossref PubMed Scopus (37) Google Scholar]. This role is consistent with BDLPs acting within the fission ring formed from the inside of the bacteria, so how was it recruited to the outside (cytosolic side) of mitochondria to drive division? Interestingly, studies in Bacillus subtilis reported the regulated recruitment of DynA to areas of membrane damage, playing critical roles in membrane repair [9Sawant P. Eissenberger K. Karier L. Mascher T. Bramkamp M. A dynamin-like protein involved in bacterial cell membrane surveillance under environmental stress.Environ. Microbiol. 2016; 18: 2705-2720Crossref PubMed Scopus (26) Google Scholar]. In addition, loss of dynA led to an increased susceptibility to phage infections, meaning that this GTPase is an important mediator of bacterial innate immunity. These studies reveal early roles for dynamin family members in closing gaps in membranes to facilitate repair, in the fusion of membrane within the cytokinetic rings, and in preventing pathogens from entering the cell. With these potential functions in mind, the BDLP family has now evolved into multiple classes of GTPases found in eukaryotic lineages, including dynamins, mitofusins (Mfns), atlastins, Mx proteins and guanylate-binding proteins (GBPs). Importantly, the most conserved BDLP family members across eukaryotes (plants, metazoans, protists, and fungi) are the mitochondrial Dnm1/Drp1 and Fzo/Mfn proteins; for example, DynA of bacteria seems closer to the mitofusins than the more distant metazoan dynamins [10Kuroiwa T. Nishida K. Yoshida Y. Fujiwara T. Mori T. Kuroiwa H. Misumi O. Structure, function and evolution of the mitochondrial division apparatus.Biochim. Biophys. Acta. 2006; 1763: 510-521Crossref PubMed Scopus (49) Google Scholar]. This is perhaps consistent with the initial role for DynA in membrane repair rather than an indicator that DynA had any role in the division of ancient mitochondria. Only when mitochondria lost their internal division machinery, later in their symbiotic evolution, did they acquire a newer version of the BDLP family, evolving as fission dynamins. What we can infer from the current analysis is that the mitochondrial-specific GTPases are closest to the bacterial forms, suggesting that the earliest new function for the archaeal dynamin family was to facilitate mitochondrial dynamics. How and why did the BDLPs begin to function at the surface of mitochondria? Consistent with bacterial DynA functioning in membrane repair, current studies on Fzo/Mfn proteins indicate that fusion is activated during cellular stress as a survival response [11Shutt T. Geoffrion M. Milne R. McBride H.M. The intracellular redox state is a core determinant of mitochondrial fusion.EMBO Rep. 2012; 13: 909-915Crossref PubMed Scopus (181) Google Scholar]. Therefore, one could imagine that the restriction of an oxygen-consuming alphaproteobacterium within a host archaeal cytoplasm may have presented some challenges that could potentially have triggered DynA recruitment to these early mitochondria, initiating the adaptation of DynA towards a more permanent mitochondrial GTPase. In addition, recent studies showed that the ectopic expression of bacterial DynA in yeast led to the tethering of the vacuole to the cell surface, indicating a capacity for DynA to facilitate interorganellar contact sites [12Burmann F. Ebert N. van Baarle S. Bramkamp M. A bacterial dynamin-like protein mediating nucleotide-independent membrane fusion.Mol. Microbiol. 2011; 79: 1294-1304Crossref PubMed Scopus (54) Google Scholar]. If mitochondria were the only intracellular organelles at the time, perhaps DynA would have triggered close contacts between mitochondria, and between mitochondria and the archaeal plasma membrane. These new contacts would have enabled the rapid flux of metabolites and lipids, and launched the beginnings of a repair mechanism for their homeostasis that likely evolved later into homotypic fusion. Consistent with this, the mitofusin family of GTPases in modern mitochondria facilitate interorganellar contact sites and drive fusion [13Naon D. Zaninello M. Giacomello M. Varanita T. Grespi F. Lakshminaranayan S. Serafini A. Semenzato M. Herkenne S. Hernandez-Alvarez M.I. et al.Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether.Proc. Natl. Acad. Sci. USA. 2016; 113: 11249-11254Crossref PubMed Scopus (307) Google Scholar]. Perhaps mitofusins have retained the capacity to drive membrane repair directly. These are just some speculative ideas on the evolutionary pressure that gave rise to the mitochondrial GTPases that are so highly conserved and essential today. Once captured within the archaea, mitochondria would have required a large amount of material for their growth and metabolic function. While there is certainly ongoing debate regarding the presence or absence of phagocytic processes within the host archaea, it is very clear that the acquisition of mitochondria would have changed the course of membrane evolution. First of all, the essential requirement for iron delivery to mitochondria to generate iron–sulfur clusters would certainly have ramped up the demand for endocytosis, and maybe even have been the major driving force for the emergence of endocytosis in the first place. With the onset of the ‘Great Oxygenation Event’ about 2.5 billion years ago, the environment became oxidizing and iron more insoluble, requiring carriers and systems to regulate iron transport into bacteria and archaea, and machineries to integrate the metal into macromolecular structures [14Harel A. Bromberg Y. Falkowski P.G. Bhattacharya D. Evolutionary history of redox metal-binding domains across the tree of life.Proc. Natl. Acad. Sci. USA. 2014; 111: 7042-7047Crossref PubMed Scopus (45) Google Scholar]. Indeed, proteins related to iron–sulfur cluster biology are among the most highly conserved genes in recent analyses of the last universal common ancestor of all cells (LUCA) [15Ilbert M. Bonnefoy V. Insight into the evolution of the iron oxidation pathways.Biochim. Biophys. Acta. 2013; 1827: 161-175Crossref PubMed Scopus (224) Google Scholar, 16Freibert S.A. Goldberg A.V. Hacker C. Molik S. Dean P. Williams T.A. Nakjang S. Long S. Sendra K. Bill E. et al.Evolutionary conservation and in vitro reconstitution of microsporidian iron-sulfur cluster biosynthesis.Nat. Commun. 2017; 8: 13932Crossref PubMed Scopus (48) Google Scholar]. Both archaea and the ancient mitochondria were addicted to iron, but mitochondria also consumed a great deal of oxygen and this would have placed a high demand for a significant increase in the availability of iron. What does this mean for the cell biology of iron transport? Bacteria and archaea use multispanning membrane iron transporters, and iron is maintained in a soluble form through the use of siderophore proteins expressed by the cells, among other mechanisms [17Braun V. Hantke K. Recent insights into iron import by bacteria.Curr. Opin. Chem. Biol. 2011; 15: 328-334Crossref PubMed Scopus (187) Google Scholar]. Would the ancient mitochondrion, with its incredible demand for iron, have obtained enough of the metal through diffusion mechanisms dependent on cell-surface transporters within the archaea? Initially, perhaps, but it would follow that this intensive demand might have initiated the earliest membrane contact site, perhaps driven by DynA as mentioned above [12Burmann F. Ebert N. van Baarle S. Bramkamp M. A bacterial dynamin-like protein mediating nucleotide-independent membrane fusion.Mol. Microbiol. 2011; 79: 1294-1304Crossref PubMed Scopus (54) Google Scholar]. By contacting the cell surface directly, mitochondria would have localized where the iron transporters reside to ensure they received a direct and adequate supply of iron. A number of studies have demonstrated the requirement for direct contact sites between the early endosome and mitochondria to facilitate the transport of iron directly, without a diffusible, cytosolic intermediate [18Sheftel A.D. Zhang A.S. Brown C. Shirihai O.S. Ponka P. Direct interorganellar transfer of iron from endosome to mitochondrion.Blood. 2007; 110: 125-132Crossref PubMed Scopus (206) Google Scholar]. In fact, cytosolic iron is stored in a high-affinity complex with ferritin and it cannot be accessed unless this iron-loaded ferritin cycles through the acidic lysosome to liberate the iron from the complex; this process may again allow transport to mitochondria through direct vacuole/lysosome contact sites. The field of mitochondrial cell biology today is actively investigating the molecular nature of a plethora of interorganellar contact sites, and the endosome is just one of them. However, I would posit that contact sites to drive iron transport might have been the first (Figure 1). While contact sites could facilitate iron delivery to early mitochondria, what about the origin of endosomes themselves? In my view, there would have been extreme evolutionary pressure for archaea to evolve a system to deliver iron specifically to mitochondria. As the numbers of mitochondria increased, these organelles would have become a serious competitor for archaeal iron consumption, considering iron metabolism is essential for archaeal survival. One obvious strategy to stop mitochondria from consuming all of the iron delivered across cell-surface transporters is to increase the surface area, ultimately invaginating the membrane to form endosomes. This would provide clear spatial separation of the iron pools for the host archaeon and endosymbiont. Internalizing additional iron into vesicles for specific delivery to mitochondria would also provide a framework to evolve mechanisms to acidify these endosomes, via vacuolar ATPases, to increase iron solubility, introducing efficiency and important new paradigms for the regulation and signaling of iron transport. Another essential adaptation for the survival of mitochondria within the archaea would have been the requirement to obtain lipids and other metabolites essential for their growth and division. Interestingly, archaeal membrane lipids are distinct from those in bacterial and eukaryotic membranes. Archaeal phospholipids are derived from isoprenoid ethers rich in sn-glycerol-1-phosphate and bacterial/eukaryotic membranes have fatty acid esters linked to sn-glycerol-3-phosphate, meaning the lipids have different chiralities [19Pereto J. Lopez-Garcia P. Moreira D. Ancestral lipid biosynthesis and early membrane evolution.Trends Biochem. Sci. 2004; 29: 469-477Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar]. Once combined in the early eukaryote, it appears that the bacterial enzymes dominated lipid biogenesis. One could argue then that early mitochondria contained the requisite machinery for their autonomous growth and division, assuming the building blocks of those reactions were readily available. It is unclear how or when the new eukaryotic cell would have adopted the mitochondrial lipid composition, but the evidence suggests that early mitochondria may have been a ready source of lipids for the archaeal host, rather than the other way around. Currently, mitochondria play an important role in the de-esterification of phosphatidylethanolamine to phosphatidylserine, but most mitochondrial lipids are obtained from the endoplasmic reticulum (ER). Evolutionary theorists posit that the ER derived from an elaboration of the plasma membrane, although it has recently been suggested that it may have emerged from the mitochondrial outer membrane [1Gould S.B. Garg S.G. Martin W.F. Bacterial vesicle secretion and the evolutionary origin of the eukaryotic endomembrane system.Trends Microbiol. 2016; 24: 525-534Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. One argument for a mitochondrial origin of the ER is the current similarity in the redox and calcium chemistry within the ER lumen and mitochondrial intermembrane space. On the other hand, the genetic analysis of Loki revealed actin-related proteins, suggesting that the archaeal plasma membrane had acquired at least some flexibility [3Zaremba-Niedzwiedzka K. Caceres E.F. Saw J.H. Backstrom D. Juzokaite L. Vancaester E. Seitz K.W. Anantharaman K. Starnawski P. Kjeldsen K.U. et al.Asgard archaea illuminate the origin of eukaryotic cellular complexity.Nature. 2017; 541: 353-358Crossref PubMed Scopus (564) Google Scholar]. This indicates that the machinery may have been present to facilitate (or elaborate) a rapid expansion of an internal membrane (endoplasmic) reticulum from the cell surface, given an appropriate evolutionary stressor. As with endosomes, the generation of contact sites between mitochondria and the emerging ER would have allowed the rapid exchange of metabolites with the archaeal ‘host’, but would also have allowed mitochondria to distribute throughout the cell (Figure 1). Importantly, these contacts would provide a means for the archaea to rapidly communicate with mitochondria even before the host genome incorporated the mitochondrial genes. While the ER is now separated from the plasma membrane, initially the ER might have been a conduit for mitochondria throughout the cell to directly respond to changes in the extracellular environment. An important consequence of an elaborated ER is the movement of the protein import machinery from the cell surface to these new internal membranes. This ultimately led to the evolution of the Sec61 translocon of modern eukaryotes. This shift of membrane protein biogenesis into the ER would have necessitated the expansion of the cellular protein secretion pathways, vesicle transport and the elaboration of the Golgi apparatus. A third immediate cellular adaptation within the endosymbiotic process would have been the host response to the vesicles being shed by the alphaproteobacterial prisoner. The process of bacterial membrane shedding has become a major area of study in the field, as it is now widely accepted that essentially all Gram-negative and at least some Gram-positive bacteria actively shed vesicles [4Kim J.H. Lee J. Park J. Gho Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles.Semin. Cell Dev. Biol. 2015; 40: 97-104Crossref PubMed Scopus (224) Google Scholar]. Indeed, this process is also conserved in present-day mitochondria, where mitochondrial-derived vesicles are understood to be an important aspect of their plasticity [20Sugiura A. McLelland G.L. Fon E.A. McBride H.M. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles.EMBO J. 2014; 33: 2142-2156Crossref PubMed Scopus (474) Google Scholar]. How would the archaea have responded to the presence of these internal vesicles? The function and composition of bacterial vesicles depends greatly on the type of bacteria, their environment, and the physiological trigger. Bacterial vesicles are used to transport content within the colony, to target toxins to invading bacteria, and (currently) to fuse with eukaryotic cells and facilitate infection [4Kim J.H. Lee J. Park J. Gho Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles.Semin. Cell Dev. Biol. 2015; 40: 97-104Crossref PubMed Scopus (224) Google Scholar]. In this context, it is interesting to consider that the release of vesicles carrying pore-forming toxins may have facilitated the initial invasion of the original alphaproteobacteria to enter the archaea in the first place. Mitochondria currently shed vesicles that can target specific cargoes to peroxisomes or to late endosomes/lysosomes, where oxidized or damaged content is degraded [20Sugiura A. McLelland G.L. Fon E.A. McBride H.M. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles.EMBO J. 2014; 33: 2142-2156Crossref PubMed Scopus (474) Google Scholar]. What the exact situation may have been in early eukaryogenesis is unknown, but perhaps the first response of the archaea would have been to package the bacterial vesicles into their own secreted vesicles to eject them from the cell [21Erdmann S. Tschitschko B. Zhong L. Raftery M.J. Cavicchioli R. A plasmid from an Antarctic haloarchaeon uses specialized membrane vesicles to disseminate and infect plasmid-free cells.Nat. Microbiol. 2017; 2: 1446-1455Crossref PubMed Scopus (67) Google Scholar]. Only once the archaea developed a hydrolytic late endosome/autophagosomal system could they have disposed of mitochondrial-derived vesicles directly. While mitochondrial-derived vesicles were the last to be discovered in modern cell biology, it is intriguing to consider that they may have been the first intracellular vesicle during eukaryogenesis. The first class of mitochondrial-derived vesicles identified were shown to target a subclass of peroxisomes. While this was a very unexpected finding, investigations into the biogenesis of peroxisomes support the idea that these organelles are an evolutionary derivative of mitochondria [22Speijer D. Reconsidering ideas regarding the evolution of peroxisomes: the case for a mitochondrial connection.Cell Mol. Life Sci. 2014; 71: 2377-2378Crossref PubMed Scopus (15) Google Scholar]. The peroxisomal enzymes involved in the beta-oxidation of fatty acids have an alphaproteobacterial lineage, indicating that they emerged after the acquisition of mitochondria. But the relationship between these two organelles is now multifaceted, from shared mechanisms of organelle division, to the nature of their contacts with the ER, and much more. One major difference between these organelles is the ability of peroxisomes to form de novo within cells. This de novo formation has long been thought to arise exclusively from the ER [23Smith J.J. Aitchison J.D. Peroxisomes take shape.Nat. Rev. Mol. Cell Biol. 2013; 14: 803-817Crossref PubMed Scopus (301) Google Scholar]; however, recent studies in mammalian cells indicate that peroxisomes are a hybrid of ER and mitochondrial-derived membranes [24Sugiura A. Mattie S. Prudent J. McBride H.M. Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes.Nature. 2017; 542: 251-254Crossref PubMed Scopus (227) Google Scholar]. In this case, mitochondrial vesicles carrying peroxisomal membrane proteins fuse with ER-derived vesicles carrying complementary peroxisomal proteins that, upon fusion, reconstitute the functional import machinery for peroxisomal maturation and growth. This provides additional support for the notion that early mitochondria may have segregated selective biochemical pathways into a new suborganelle that evolved into the peroxisomes we know today [22Speijer D. Reconsidering ideas regarding the evolution of peroxisomes: the case for a mitochondrial connection.Cell Mol. Life Sci. 2014; 71: 2377-2378Crossref PubMed Scopus (15) Google Scholar]. Given the highly reactive nature of these biochemical pathways, including beta-oxidation of fatty acids, the specific segregation and removal of these enzymes from mitochondria within vesicles would have helped to protect mitochondrial genomes from oxidative damage, ultimately giving rise to an entirely new intracellular organelle. Overall, the appearance of the mitochondria within the ancient archaea would have introduced a series of cell biological challenges that would have required the rapid adaptation of new membrane biology for the endosymbiont to survive and flourish. It could be argued that the ability of an organism to defend itself represents one of the earliest evolutionary adaptations. Bacteria evolved the CRISPR–Cas9 system to edit the genome of infectious bacteriophages, providing an adaptive immune response to fight future infections [25Wiedenheft B. Sternberg S.H. Doudna J.A. RNA-guided genetic silencing systems in bacteria and archaea.Nature. 2012; 482: 331-338Crossref PubMed Scopus (1305) Google Scholar]. Indeed, the elucidation of this adaptive response in bacteria has revolutionized molecular biology and medicine. However, CRISPR–Cas9 is just one of many immune mechanisms found in bacteria. Indeed, a recent systems-based interrogation of bacterial genomes led to the identification of nine previously unknown immune response mechanisms to fight bacteriophages, highlighting the depth and conservation of these processes [26Doron S. Melamed S. Ofir G. Leavitt A. Lopatina A. Keren M. Amitai G. Sorek R. Systematic discovery of antiphage defense systems in the microbial pangenome.Science. 2018; 359 (pii: eaar4120)Crossref Scopus (393) Google Scholar]. It is fascinating to think about each of these modes of immunity from an evolutionary perspective. One of the early cell biological responses to phage infection, environmental stress or invasion by other bacterial species is for the target bacteria to shed vesicles [4Kim J.H. Lee J. Park J. Gho Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles.Semin. Cell Dev. Biol. 2015; 40: 97-104Crossref PubMed Scopus (224) Google Scholar]. The vesicles contain many types of cargoes, most notably toxins like anthrax, enterotoxins, or enzymes that digest the surface of invading bacterial species. For example, Pseudomonas aeruginosa vesicles carry murein hydrolase, which degrades the peptidoglycan surface of both Gram-positive and Gram-negative bacteria [4Kim J.H. Lee J. Park J. Gho Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles.Semin. Cell Dev. Biol. 2015; 40: 97-104Crossref PubMed Scopus (224) Google Scholar]. For the invading pathogen, bacterial vesicles are central players in facilitating infection by fusing with (or being internalized into) target cells. Either hydrolases or pore-forming toxins, for example, would permeabilize the target cell surface, allowing subsequent entry by the invading bacteria [4Kim J.H. Lee J. Park J. Gho Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles.Semin. Cell Dev. Biol. 2015; 40: 97-104Crossref PubMed Scopus (224) Google Scholar]. Bacterial and archaeal membrane vesicles can also carry genetic material, potentially facilitating horizontal gene transfer between species [21Erdmann S. Tschitschko B. Zhong L. Raftery M.J. Cavicchioli R. A plasmid from an Antarctic haloarchaeon uses specialized membrane vesicles to disseminate and infect plasmid-free cells.Nat. Microbiol. 2017; 2: 1446-1455Crossref PubMed Scopus (67) Google Scholar, 27Bitto N.J. Chapman R. Pidot S. Costin A. Lo C. Choi J. D’Cruze T. Reynolds E.C. Dashper S.G. Turnbull L. et al.Bacterial membrane vesicles transport their DNA cargo into host cells.Sci. Rep. 2017; 7: 7072Crossref PubMed Scopus (159) Google Scholar]. Indeed, the inclusion of DNA within vesicles provides an important clue to suggest that mitochondrial-derived vesicles could facilitate the transfer of mitochondrial genes to the archaeal host genome. But could these ancient responses have played a pivotal role in the development of a complex endomembrane system? Phage outnumber bacteria by 10 to 1, and the rapid and counter responses between these organisms is considered to be a major driving force in evolution. Therefore, the immune systems within the archaea and the alphaproteobacteria would have rapidly synergized to ensure survival. Adaptations in membrane biology are very likely to have been a major part of this evolving arsenal. For example, the pressure for the archaea to acquire an elaborated endomembrane system to accommodate the mitochondria would have provided a new mechanism to engulf and digest viruses, and ultimately other bacteria. The study of host–pathogen interactions has continually informed us of novel principles in cell biology, and it is almost certain that the earliest host–pathogen interactions sculpted the endomembrane system within the emerging eukaryote. As the two immune systems synergized, what then became of the mitochondrial contribution to immunity? Certainly, the alphaproteobacterial ancestor of mitochondria also carried a complete immune system upon entry into the archaea. Any genetic adaptations along the lines of CRISPR–Cas9 were likely lost as the genes were transferred to the archaeal genome. However, mitochondria have retained a critical role as an early sentinel of any infectious breach, rapidly communicating this information to the nucleus [28Mills E.L. Kelly B. O’Neill L.A.J. Mitochondria are the powerhouses of immunity.Nat. Immunol. 2017; 18: 488-498Crossref PubMed Scopus (513) Google Scholar]. Beyond an established contribution of mitochondrial reactive oxygen species (ROS) to innate signaling pathways, an early advance was the identification of the mitochondrial antiviral signaling protein MAVS as an essential driver of the response to infections with double-stranded RNA viruses. MAVS is anchored in the mitochondrial outer membrane (and peroxisomal membrane) and is essential to co-ordinate the assembly of signaling complexes on the mitochondrial surface that ultimately activate the global transcriptional response to viral infection [28Mills E.L. Kelly B. O’Neill L.A.J. Mitochondria are the powerhouses of immunity.Nat. Immunol. 2017; 18: 488-498Crossref PubMed Scopus (513) Google Scholar]. In addition to antiviral immunity, the innate pathways downstream of bacterial infection were shown to involve the recruitment of signaling complexes like the inflammasome to the mitochondrial surface. More recently, it has been realized that mitochondrial DNA itself acts as a potent activator of inflammation when released into the cytoplasm, within the endosome or when released from the cell [28Mills E.L. Kelly B. O’Neill L.A.J. Mitochondria are the powerhouses of immunity.Nat. Immunol. 2017; 18: 488-498Crossref PubMed Scopus (513) Google Scholar]. And lastly, mitochondrial content delivered to the late endosome through mitochondrial-derived vesicles can be processed and loaded on MHC class I molecules, launching an adaptive immune response to infection or heat stress [29Matheoud D. Sugiura A. Bellemare-Pelletier A. Laplante A. Rondeau C. Chemali M. Fazel A. Bergeron J.J. Trudeau L.E. Burelle Y. et al.Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation.Cell. 2016; 166: 314-327Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar]. This vesicle response to infection is perhaps a remnant of the alphaproteobacterial reaction to invasion. In considering the ancient set of immune responses within the early mitochondria, we should not be surprised that they have retained such a central role in mediating immune responses within the modern eukaryote. The mechanisms that drive each of these processes remain under intense investigation, but perhaps our understanding of these pathways could be guided in part through an evolutionary lens. For example, the Mx and GBP families of GTPases descended from the BDLP family described above are interferon-induced genes expressed only after infection, acting within the immune response pathway [30Meunier E. Broz P. Interferon-inducible GTPases in cell autonomous and innate immunity.Cell Microbiol. 2016; 18: 168-180Crossref PubMed Scopus (76) Google Scholar]. Very little is known about these GTPase families, including when they evolved or which membranes they act upon first. Wouldn’t it be interesting if they had evolved earlier than the mitofusin family? If so, this might suggest the earliest demand for mitochondrial dynamics was during infection, and the steady-state fusion process may have been a later adaptation. This highlights the importance of detailed phylogenetic analysis of these gene families to help understand the motivations that drove adaptations in cell biology. For now, it is clear that there is a robust, signaled response of mitochondria to infection that has helped shape the dynamic responses of these interconnected organelles throughout evolution. From the perspective of a mitochondrial cell biologist, it has been a challenge to understand why these metabolic factories display such a complex array of dynamic behaviors. While much of this editorial has been speculative, there is no question that the acquisition of this oxygen-breathing, ROS-producing energy generator was the turning point in cellular evolution that forced considerable change within the archaea. Therefore, there is a certain logic in thinking that a great deal of modern cell biology evolved to serve and protect mitochondria. The success of this union depended upon rapid adaptation and the emergence of highly dynamic, complex internal membranes. This editorial took a step back through time to think about the origin of the eukaryotic cell in an attempt to imagine the earliest motivations of the ancient eukaryotes to generate internal membranes. As the old adage goes “you don’t know where you’re going until you know where you’ve been”. So we must look to the past for insights into the exciting new discoveries in cell biology today.
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