Am J Physiol Cell Physiol 305: C909–C915, 2013.
First published July 24, 2013; doi:10.1152/ajpcell.00216.2013.
Themes
Evolution and cell physiology. 2. The evolution of cell signaling: from
mitochondria to Metazoa
Neil W. Blackstone
Department of Biological Sciences, Northern Illinois University, DeKalb, Illinois
Submitted 15 July 2013; accepted in final form 17 July 2013
endosymbiosis; eukaryotes; metabolic signaling; mitochondria; multicellularity
“The dynamic equilibrium (or, better, the unceasing competition) among
cells in a multicellular assemblage is mediated by cell signaling.”
Perspectives in Animal Phylogeny and Evolution,
Alessandro Minelli (40)
is a history of levels-of-selection transitions:
genes within chromosomes, chromosomes within simple cells,
simple cells within complex cells, and complex cells within
multicellular organisms (14, 21, 23, 35–37, 42, 44). This
conceptualization allows commonalities to emerge that might
otherwise be missed; e.g., bacteria can be the particles within
the eukaryotic collective, or eukaryotes can be the particles
within the multicellular collective (Fig. 1). Thus, parallels can
be expected between these seemingly distinct major transitions. Such parallels may be particularly likely, because each
THE HISTORY OF LIFE
Address for reprint requests and other correspondence: N. W. Blackstone,
Dept. of Biological Sciences, Northern Illinois Univ., DeKalb, IL 60115
(e-mail: [email protected]).
http://www.ajpcell.org
transition requires mechanisms that mediate conflict among the
lower-level units. Conflicts arise because selection on lowerlevel units can favor competition, rather than cooperation.
Competition for substrate is particularly likely; the lower-level
unit that obtains more substrate can achieve an advantage in
replication rate and outcompete other lower-level units. As
described by Michod (38), conflicts can be mediated by mechanisms that decrease heritable variation of the lower-level units
(making selfish behavior less likely to evolve) or increase
heritable variation of higher-level units (making cooperative
groups more likely to be favored).
In the many independent origins of multicellular eukaryotes,
cell signaling can be regarded as a mechanism of conflict
mediation (see epigraph; 14, 37, 40). For instance, signaling
pathways that govern germ line formation and sequestration
limit the extent to which selfish lower-level units can form by
mutation and gain access to the next generation. More broadly,
any pathway that downregulates cell division also diminishes
the likelihood that selfish lower-level units will form by mutation. Policing (e.g., programmed cell death pathways) provides an alternative mechanism to hold selfish lower-level units
in check.
Were such signaling pathways created de novo? An evolutionary view might deem this unlikely, since similar conflicts
had to be mediated in the origin of eukaryotes. Perhaps eukaryotic multicellularity could be achieved so easily relative to
the origin of eukaryotes precisely because the latter preceded
the former (8). By this view, the roots of cell signaling in all
multicellular eukaryotes may be found in the mechanisms that
mediated conflict in early eukaryotes. Hence, to understand the
roots of cell signaling, the mechanisms of conflict mediation in
eukaryotes must be understood. To this end, the endosymbiont
hypothesis will be briefly reviewed, with attention to its beginnings as an alternative to “Darwinian” conflict. Then the
nature of the conflicts, as well as likely mechanisms of conflict
mediation, will be examined. Finally, the relevance to cell
signaling in multicellular eukaryotes will be revisited.
The Endosymbiont Hypothesis
Early and late 20th century discussion of the endosymbiont
theory seems to share a disdain of Darwin’s theory, in general,
and the notion of conflict, in particular. For instance, Wallin
(52) wrote, “Modern writers have recognized the insufficiency
of Darwin’s hypothesis to explain the origin of species. The
‘unknown factor’ in organic evolution has been especially
emphasized by Osborne, Bateson, Kellog, and other recent
writers. This ‘unknown factor’ is especially concerned with the
origin of species.” Over a half-century later, and subsequent to
Margulis’ resurrection of the endosymbiont hypothesis (31),
Margulis and Sagan (32) wrote, “Next, the view of evolution as
chronic bloody competition among individuals and species, a
0363-6143 /13 Copyright © 2013 the American Physiological Society
C909
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Blackstone NW. Evolution and cell physiology. 2. The evolution
of cell signaling: from mitochondria to Metazoa. Am J Physiol Cell
Physiol 305: C909 –C915, 2013. First published July 24, 2013;
doi:10.1152/ajpcell.00216.2013.—The history of life is a history of
levels-of-selection transitions. Each transition requires mechanisms
that mediate conflict among the lower-level units. In the origins of
multicellular eukaryotes, cell signaling is one such mechanism. The
roots of cell signaling, however, may extend to the previous major
transition, the origin of eukaryotes. Energy-converting protomitochondria within a larger cell allowed eukaryotes to transcend the
surface-to-volume constraints inherent in the design of prokaryotes.
At the same time, however, protomitochondria can selfishly allocate
energy to their own replication. Metabolic signaling may have mediated this principal conflict in several ways. Variation of the protomitochondria was constrained by stoichiometry and strong metabolic
demand (state 3) exerted by the protoeukaryote. Variation among
protoeukaryotes was increased by the sexual stage of the life cycle,
triggered by weak metabolic demand (state 4), resulting in stochastic
allocation of protomitochondria to daughter cells. Coupled with selection, many selfish protomitochondria could thus be removed from
the population. Hence, regulation of states 3 and 4, as, for instance,
provided by the CO2/soluble adenylyl cyclase/cAMP pathway in
mitochondria, was critical for conflict mediation. Subsequently, as
multicellular eukaryotes evolved, metabolic signaling pathways employed by eukaryotes to mediate conflict within cells could now be
co-opted into conflict mediation between cells. For example, in some
fungi, the CO2/soluble adenylyl cyclase/cAMP pathway regulates the
transition from yeast to forms with hyphae. In animals, this pathway
regulates the maturation of sperm. While the particular features
(sperm and hyphae) are distinct, both may involve between-cell
conflicts that required mediation.
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popular distortion of Darwin’s notion of ‘survival of the
fittest,’ dissolves before a new view of continual cooperation,
strong interaction, and mutual dependence among life forms.
Life did not take over the globe by combat, but by networking.
Life forms multiplied and complexified by co-opting others,
not by killing them.” Interestingly, despite the extensive development of level-of-selection theory between 1986 and 2001
(14, 23, 35–37, 44), Margulis did not seem to change her views
and later published an identically worded statement (33).
Margulis’ endorsement of the endosymbiont theory met with
extensive scientific criticism (11, 45, 50). Perhaps, surprisingly, none of these authors criticized the endosymbiont hypothesis on general evolutionary grounds, i.e., because stable
symbiosis was unlikely due to conflicts between levels of
selection. This is particularly surprising, because, in the 1960s,
and 1970s, there was near-absolute condemnation of any kind
of group-selection thinking in evolutionary theory (34, 53). As
nucleotide sequence data built overwhelming support for the
endosymbiont hypothesis (20, 48, 55), the issue of conflict
began to emerge. As pointed out by Williams (54), “The
subsequent stability of these eukaryotic cell lineages through
geologic time, despite potential disruption from selection
among cellular components, presents an evolutionary problem
that deserves detailed attention.” Earlier (16) and later (7)
comments in the same vein had equally little impact. Rather,
the empirical discovery of the role of mitochondria and cytochrome c release in programmed cell death (25, 56) firmly
established the notion of conflicting relationships in the formation of the eukaryotic cell (18, 26, 39). A careful reexamination of the evolutionary conflicts inherent in the origin of
eukaryotes constitutes the first step toward consideration of the
mediation of these conflicts.
Conflict and Mediation in the Origin of Eukaryotes
Prokaryotes suffer from at least one serious design limitation:
their energy-converting membranes are on the outside of the cell.
Any increase in size thus results in relatively less surface for
carrying out energy conversion and relatively more volume requiring such conversion (28). These constraints can be transcended, if small, energy-converting cells reside within a larger
one. A clever engineering solution to surface-to-volume constraints, however, results in a levels-of-selection nightmare. Because the protomitochondria now carry out energy conversion and
allocation, selection will inexorably favor the protomitochondrion
Fig. 2. Metabolic complementation between a protomitochondrion and the
cytosol of the protoeukaryote. Substrate is taken up from the environment (1)
and oxidized and excreted as waste (2a). An electron carrier, X, is reduced (3)
and then taken up by the protomitochondrion and oxidized (4). The cytosol and
the protomitochondrion carry out energy conversion in this fashion. Stoichiometry prevents defection of the lower-level units because of the necessary
complementation of redox reactions. As the protoeukaryote evolves, waste
may be taken up by the protomitochondrion (2b), rather than excreted.
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Fig. 1. Two higher-level units (large circles) containing two kinds of lowerlevel units ( and Œ). In the emergence of a higher-level unit, conflicts among
the lower-level units can be mediated in two ways (38): 1) by mechanisms that
decrease the heritable variation of the lower-level units (making selfish
behavior less likely to evolve) or 2) by mechanisms that increase the heritable
variation of higher-level units (making cooperative groups more likely to be
favored by selection).
that allocates energy to its own selfish replication. If such variant
protomitochondria are not held in check by mechanisms of conflict mediation, the symbiosis will fail.
Discussion of conflict mediation has largely focused on the
transfer of the mitochondrial genome to the nucleus (27).
Doubtless, this transfer and the consequent reduction in the
mitochondrial genome and mutational space did diminish the
heritable variation of the lower-level units. Close examination,
however, reveals difficulties with the hypothesis that genome
loss was the primary mechanism of conflict mediation (8).
First, all modern mitochondria that function in energy conversion retain a small genome (2, 3), so they retain some heritable
variation. Second, before a functional protomitochondrion can
lose any heritable variation, the mitochondrial protein-import
apparatus has to evolve. This is a nontrivial system. Furthermore, it is difficult to conceive of selection driving its formation, except in a protoeukaryote that had already mediated
conflicts and begun to emerge as a higher-level unit. Generally,
the role of selection presents the biggest obstacle for genome
loss evolving to mediate conflicts: if there is a selfish advantage
for a protomitochondrion to retain a gene, how did selection
then lead to gene loss? In this context, various arguments can
be contrived, but as long as strong selection acted on protomitochondria, loss of heritable variation remained unlikely (8).
In contrast, metabolic regulation seems considerably more
plausible (8). Energy metabolism can be regarded as a series of
living redox couples that are linked to environmental sources
and sinks of electrons (2). To the extent that replication
requires energy (5, 29, 47), replication is regulated by the
environment. In the case of the protomitochondria, the environment is the cytosol. A symbiosis based on metabolic complementation (17) provides a predictable framework for the
interaction of the mutualistic partners (Fig. 2). Substrate is
taken up into the cytosol. Energy-converting processes then
oxidize the substrate, resulting in the reduction of an electron
carrier. The reduced electron carrier is subsequently taken up
by a protomitochondrion and oxidized by its energy-converting
processes. Finally, the oxidized electron carrier is excreted by
Themes
CELL SIGNALING AND EVOLUTION
species are produced under these conditions. Damage to protomitochondria would ensue, enhancing the rate at which protomitochondria were consumed by the cytosol, balancing the
energy budget of the protoeukaryote.
Under these circumstances, the evolution of the adenine
nucleotide translocator (ANT) would be adaptive for the individual protomitochondrion. Because ANT exchanges ATP in
protomitochondria with ADP in the cytosol, a protomitochondrion with ANT could effectively generate metabolic demand,
maintain metabolic state 3, and avoid state 4. Protomitochondria with ANT would be less likely to damage themselves and
be consumed by the cytosol. This would translate into a lower
mortality rate. If ANT-containing protomitochondria replicated
at the same rate as those that did not contain ANT, the ANTcontaining protomitochondria would come to predominate because of lower mortality rates (Fig. 3). Ion exchangers that
diminish the transmembrane proton gradient (e.g., the mitochondrial Ca2⫹ uniporter) also simulate metabolic demand and may
have evolved under selective dynamics similar to ANT.
Likely more than any other factor, the evolution of ANTcontaining protomitochondria transformed the protoeukaryote.
Energy conversion in the cytosol became less and less important. Increasingly, the cytosol became devoted to two tasks:
1) providing protomitochondria with substrate and 2) converting the ATP exported from protomitochondria back to ADP.
As discussed above, given its position at the top of the food
chain, the protoeukaryote was likely well equipped for task 1.
Equally crucial was task 2; if the cytosol could not utilize the
available ATP, ANT-containing protomitochondria would lose
their advantage over those that did not contain ANT. Successful protoeukaryotes likely consumed this ATP by maintaining
a high replication rate and by developing an energetically
expensive store of information (29, 30).
Nevertheless, under some environmental conditions, the
metabolic demand of the cytosol may have slackened. Without
ADP to import, even ANT-containing protomitochondria
would enter state 4. ANT-less protomitochondria would no
longer be at a disadvantage. The extensive production of
reactive oxygen by the community of protomitochondria, possibly enhanced by cytochrome c release (9), may have caused
sufficient damage to the protoeukaryote, such that a sexual
phase of the life cycle would have evolved (10). As commonly
found in unicellular eukaryotes, sex likely involved fusion of
two protoeukaryotes and recombination. Sex also likely randomly apportioned protomitochondria to the two daughter
cells. By chance, the variance between the higher-level units
may be increased, so that the ANT-less protomitochondria
would be disproportionately found in one of the daughter cells
Fig. 3. Acquisition of the adenine nucleotide
translocator (ANT) by a protomitochondrion.
In the specialized environment of the cytosol,
protomitochondria were typically oversupplied
with substrate. Without ANT, these protomitochondria converted the available supply of
ADP to ATP and entered state 4. Protomitochondria were damaged by high levels of reactive oxygen species followed by consumption by the cytosol. With ANT, protomitochondria could maintain state 3 by exporting
ATP. Such protomitochondria had a lower
mortality rate and increase in frequency in the
cytosol.
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the protomitochondrion, and the cycle can be repeated. Both
partners reap benefits from this sort of metabolic complementation. At the same time, neither partner can easily defect from
the cooperative aspects of the relationship without losing the
benefits as well. Such metabolic complementation constrains
the variation of the protomitochondria through simple stoichiometry. Evolution of selfish protomitochondria in these circumstances thus seems unlikely.
Given that the central limitation of prokaryotes is the presence of energy-converting membranes on the outside of the
cell, a key innovation of eukaryotes was the loss of the
energy-converting function of the plasma membrane. Once this
occurred, the cytosol could not be supplied with ATP derived
from chemiosmosis. The cytosol could still carry out substratelevel phosphorylation. If the environment is very rich in
electron donors, substrate-level phosphorylation may provide
an efficient mechanism to exploit it (e.g., yeast and cancer
cells). Indeed, since size increase likely drove the evolution of
eukaryotes (8, 12), the protoeukaryote was likely larger than all
other contemporaneous cells. Consuming these smaller cells
may have provided the protoeukaryote with abundant substrate. Nevertheless, at some point, a protoeukaryote population would likely deplete these abundant resources. In a somewhat depleted environment, substrate-level phosphorylation in
the cytosol would be out-of-balance with oxidative phosphorylation in the protomitochondria. Energetic accounts could be
rectified if, periodically, some of the protomitochondria were
consumed by the cytosol. Indeed, such a process occurs in
modern cells in the form of mitophagy (19).
In an environment that provided sufficient, but not unlimited, substrate, the imbalance between the cytosol and the
protomitochondria might have other consequences. If the cytosol were carrying out substrate-level phosphorylation while
the protomitochondria were carrying out oxidative phosphorylation and if both were utilizing the same (limited) substrate
stream (pathway 2b in Fig. 2), the protomitochondria would
likely have an enormous oversupply of ATP. This follows
because oxidative phosphorylation yields much more ATP per
molecule of substrate. With unlimited substrate, rapid processing via substrate-level phosphorylation might allow the cytosol
to balance this greater yield. If substrate is not unlimited,
however, the protomitochondria will have an excess of ATP
relative to the cytosol. Under these conditions, protomitochondria would be maintained in metabolic state 4. Relative to the
supply of substrate, there would be little metabolic demand and
high levels of ATP relative to ADP and of NADH relative to
NAD⫹, and the electron carriers of the electron transport chain
would be highly reduced. High levels of reactive oxygen
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(Fig. 4). Subsequent selection would, of course, favor the more
cooperative group, i.e., the protoeukaryote with a greater proportion of ANT-containing protomitochondria.
To summarize, once ANT evolved, conflict in the protoeukaryote was mediated by metabolic state. High metabolic
demand led to state 3 and constrained the variation of the
lower-level units, favoring cooperation. Low metabolic demand led to state 4 and increased the variation of the higherlevel units via sex. Selection subsequently favored the more
cooperative protoeukaryotes. Given the critical nature of the
state 3-to-state 4 transition, selection for additional mechanisms that regulate this metabolic transition would occur.
In this context, consider the CO2/soluble adenylyl cyclase
(sAC)/cAMP pathway (Fig. 5A). In eukaryotic mitochondria
(1), CO2 produced by the oxidation of substrate in the tricarboxylic acid (Krebs) cycle is converted by carbonic anhydrases
to bicarbonate. Bicarbonate, in turn, stimulates sAC to form
cAMP. cAMP then activates protein kinase A, which phosphorylates various mitochondrial proteins that are integral to or
associated with the electron transport chain. As a result, the
oxidation of substrate and reduction of coenzymes closely
correspond to the activity of the electron transport chain. If a
large quantity of substrate is oxidized and the NAD⫹ pool
becomes relatively reduced, high levels of activity of the
mitochondrial electron carriers quickly oxidize the NADH.
Metabolic state 3 is thus maintained and state 4 is avoided even
as the substrate supply rapidly changes.
The CO2/sAC/cAMP pathway is found in modern cyanobacteria (13) and may have been present in the ancestors of the
protomitochondria prior to the endosymbiosis. No doubt, this
pathway provides efficient utilization of substrate and regulation of reactive oxygen production in free-living bacteria. As
the endosymbiosis progressed, however, these functions became even more critical. As the cytosol became more specialized in providing substrate for protomitochondria, at times the
supply of substrate may have strained the capacity of protomitochondria to process it. At the same time, the association
between metabolic state 4 and consumption by the cytosol
required efficient metabolic regulation. The CO2/sAC/cAMP
Fig. 5. The CO2/soluble adenylyl cyclase (sAC)/
cAMP pathway functions in bacteria to efficiently
utilize substrate and minimize reactive oxygen
species production (A). CA, carbonic anhydrase;
I–IV, complexes I–IV of the mitochondrial electron transport chain (from Ref. 1). In protomitochondria, this pathway mediated conflict by maintaining state 3 and averting state 4 as the supply of
substrate from the cytosol varied. As multicellular
eukaryotes evolved repeatedly, this pathway was
co-opted to mediating conflicts between cells in
germ cell formation and maturation in animals (B)
and between nuclei in the transition from yeast to
hyphal growth in fungi (C).
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Fig. 4. Impact of the sexual stage of the protoeukaryotic life cycle on protomitochondria. Two protoeukaryotes with low metabolic demand suffer from the
proliferation of ANT-less protomitochondria, as well as the release of reactive oxygen and, possibly, cytochrome c from the ANT-containing protomitochondria.
These protoeukaryotes fuse and undergo whole-genome recombination. Protomitochondria are randomly distributed to the two daughter protoeukaryotes. By
chance, one daughter cell inherits more ANT-containing protomitochondria, while the other inherits more ANT-less protomitochondria. The increased variance
among the higher-level units allows selection to favor the former protoeukaryote, leading to greater cooperation and less competition among protomitochondria.
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CELL SIGNALING AND EVOLUTION
pathway thus became a key component of metabolic conflict
mediation in the emerging protoeukaryote.
Cell Signaling in Multicellular Eukaryotes
primordial interactions of protomitochondria and protoeukaryotes involving reactive oxygen species. This seems unlikely, however, since similar processes are found fully developed in unicellular eukaryotes (41). More likely, a pathway
serving a different function (or no function at all) in unicellular
eukaryotes (41) was independently co-opted into a policing
function in plants and animals. By this view, support is again
found for the hypothesis that pathways once mediating conflicts in protoeukaryotes can be recruited to a similar role in
multicellular organisms.
Ca2⫹ signaling pathways are also known to be widely distributed in eukaryotes. In the absence of available ADP, protomitochondria may have released Ca2⫹ to diminish the transmembrane
proton gradient and avoid metabolic state 4. Arguably, the complex interplay between Ca2⫹ signaling and metabolic state in
modern eukaryotes arose from this interaction. In animals, at least,
the link between Ca2⫹ signaling and cell growth and proliferation
(6) suggests a connection to mediation of levels-of-selection
conflicts. Beyond animals, the specifics of Ca2⫹ signaling are
poorly known in many groups. For the many protein components
of this signaling system, pumps and exchangers, plasma membrane channels, organelle channels, and buffers, among others,
Collins and Meyer (15) carried out a phylogenetic analysis of the
eukaryotic orthologs of the human genes for these proteins. Their
analysis strongly supports the idea that the first eukaryotes utilized
Ca2⫹ signals and points to some interesting evolutionary patterns.
For instance, Ca2⫹-regulated PLC␦, which can produce inositol
triphosphate (IP3), is more broadly distributed and possibly arose
earlier than the IP3 receptor. The hydrolysis of phosphoinositide
lipids by PLC may thus have had more ancient roles than the
current role of producing IP3 to bind to the IP3 receptor and trigger
Ca2⫹ release. As eukaryotes diversified, signaling pathways themselves underwent substantial evolutionary change.
In any event, additional clarification of the role of Ca2⫹
signaling, as well as other mitochondrial pathways in levelsof-selection conflicts, awaits further work in diverse multicellular eukaryotes. Some added insight into the role of metabolic
signaling, however, can be obtained by pathophysiological
evidence in animals. For instance, in diseases that involve
levels-of-selection conflicts, is metabolic regulation also perturbed? Extensive discussion of the “Warburg effect” in recent
years suggests that such a connection may indeed exist. The
increasing recognition that the metabolic features of cancer
cells may be generally found in proliferating mammalian cells
does not diminish the significance of this connection. For
instance, evidence suggests that the mitochondria of highly
proliferative macrophages are inhibited by nitric oxide (43). In
contrast to the above discussion of protoeukaryotes, proliferation thus seems to correspond to state 4, while differentiation
corresponds to state 3. Such a correspondence of metabolic state
and proliferation makes sense, given the much greater access of
animals than single cells to large quantities of substrate. Highly
proliferative glycolytic cells in state 4 are heavily dependent on a
rich stream of nutrients. They require these nutrients from the
organism and, thus, may be more easily regulated by the higherlevel unit. It follows that cancer cells are characterized by mutations that allow them to trigger vascularization and circumvent the
mechanisms that would usually limit their access to the necessary
nutrient resources (51).
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The evolution of multicellularity has much in common with
the evolution of eukaryotes (35, 36). Both transitions involved
selection for increased size and concomitant ecological advantages (27). As in eukaryotes, lower-level units in multicellular
organisms can be selfish in terms of energy and replication.
Nevertheless, there is one striking difference between these
major transitions: eukaryotes only evolved once and, hence, are
monophyletic, while multicellular eukaryotes evolved many
times in diverse eukaryotic lineages. Mediation of conflicts in
the origin of eukaryotes appears to have been extremely challenging but, by contrast, was relatively easy in the origin of
multicellular eukaryotes (8). This difference seems even more
remarkable, in that a structure analogous to the eukaryotic
nucleus never evolved in any multicellular lineage. In a multicellular organism, levels-of-selection conflicts thus can never
be mediated by genome transfer. On the other hand, while
metabolism of a multicellular organism is vastly more complex
than metabolism of a single cell, metabolic signaling can still
be employed to mediate conflicts. In this case, pathways of
metabolic regulation in eukaryotes can be coopted again and
again as multicellularity evolves repeatedly.
Consider again the CO2/sAC/cAMP pathway (Fig. 5). CO2/
sAC/cAMP signaling is found in animals, where, among many
other functions, it influences the development of sperm (49).
Features of sperm and spermatogenesis are derived for animals
(4), so involvement of CO2/sAC/cAMP in sperm development
is likely also derived. At the same time, CO2/sAC/cAMP
signaling is also found in fungi and mediates the transition
from unicellular to multinucleate, filamentous forms (24).
While fungi and animals are opisthokonts, the hyphae that
characterize filamentous forms do not resemble any kind of
animal multicellularity. We can thus expect that hyphal structures and the role of the CO2/sAC/cAMP pathway in their
differentiation were independently derived from animals. Nevertheless, in both cases, germ line formation in animals and
multinucleate hyphae formation in fungi, potential levels-ofselection conflicts require mediation. In a multicellular organism, constituent cells inevitably compete to form the next
generation. By setting aside the cells that will do this and by
limiting the mutational variation of cells, the germ line mediates conflicts in many animals (14, 37). Similarly, multinucleate hyphae invite competition among constituent nuclei. Mechanisms [e.g., septa (14)] are required to mediate this competition. Possibly such mediation evolved by co-opting a
protomitochondrial pathway of metabolic signaling. These
sorts of data support the larger hypothesis.
Many other potential examples can be found in signaling
pathways that involve mitochondria and are also used in
between-cell signaling in animals (8). For the most part, it is
not known how widely distributed these pathways are in other
multicellular eukaryotes. For pathways that are known to be
widely distributed, unraveling the complex evolutionary histories remains challenging. Programmed cell death provides a
case in point. While best known in animals, similar forms of
cell death are found in plants as well (46). Possibly, these
pathways evolved independently in plants and animals from
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CONCLUSIONS
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author.
AUTHOR CONTRIBUTIONS
N.W.B. prepared the figures; N.W.B. drafted the manuscript; N.W.B. edited
and revised the manuscript; N.W.B. approved the final version of the manuscript.
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The origins of eukaryotes and of multicellularity show a
number of parallels, yet they diverge sharply in one respect: the
latter evolved a number of times, while the former evolved
only once. Evolution is a historical process: could it be that
multicellularity is a relatively simple transition precisely because it was preceded by the origin of eukaryotes? Since
conflict mediation is a crucial aspect of every major transition,
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