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The Evolution of Per-cell Organelle Number

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 MINI REVIEW
published: 18 August 2016
doi: 10.3389/fcell.2016.00085

The Evolution of Per-cell Organelle

Number
Logan W. Cole *

Department of Biology, Indiana University, Bloomington, IN, USA

Organelles with their own distinct genomes, such as plastids and mitochondria, are
found in most eukaryotic cells. As these organelles and their host cells have evolved,
the partitioning of metabolic processes and the encoding of interacting gene products
have created an obligate codependence. This relationship has played a role in shaping
the number of organelles in cells through evolution. Factors such as stochastic
evolutionary forces acting on genes involved in organelle biogenesis, organelle–nuclear
gene interactions, and physical limitations may, to varying degrees, dictate the selective
constraint that per-cell organelle number is under. In particular, coordination between
nuclear and organellar gene expression may be important in maintaining gene product
stoichiometry, which may have a significant role in constraining the evolution of this trait.
Keywords: plastid, mitochondria, stoichiometry, organelle biogenesis, evolutionary cell biology

INTRODUCTION
With a few exceptions (Cavalier-Smith, 1987; Karnkowska et al., 2016), mitochondria or plastids
Edited by:
are found in all eukaryotic cells. As these organelles and their host cells have evolved together, the
Alessandro Minelli,
University of Padua, Italy
partitioning of metabolic processes and the encoding of interacting gene products have created an
obligate codependence. This relationship has obviously played an important role in shaping the
Reviewed by:
genomes of these different compartments (Howe et al., 2002; Adams and Palmer, 2003), but what
Jordan Okie,
Arizona State University, USA
has not been widely considered is how this intimate relationship has constrained the number of
Pedro Martinez, organelles in a cell through evolution.
University of Barcelona, Spain Typically, a multicellular eukaryote has hundreds or thousands of these organelles in each of
*Correspondence: their cells. These numbers not only vary among species but also among tissue types (Veltri et al.,
Logan W. Cole 1990; Li et al., 2001; Moller, 2004) and temporally during the cell cycle, across development, and in
lwcole@indiana.edu response to stress (Holloszy, 1967; Posakony et al., 1977; Boffey and Leech, 1982; Visser et al., 1995;
Moller, 2004; Kowald and Kirkwood, 2011). These organelles serve necessary metabolic functions
Specialty section: and create gene products that are necessary not only for their own function but for that of the entire
This article was submitted to cell. This, along with the transfer of genes from the organelle to nuclear genomes over evolutionary
Evolutionary Developmental Biology, time (Blanchard and Schmidt, 1995; Howe et al., 2002; Adams and Palmer, 2003), has created a
a section of the journal
necessary coordination between these entities. These factors, to some extent, have constrained the
Frontiers in Cell and Developmental
Biology
number of organelles in a cell through selection. Other factors, such as stochastic evolutionary
forces, which vary depending on the population genetic environment of the genes involved in
Received: 08 June 2016
organelle biogenesis and organelle–nuclear interactions, or physical limitations may obscure the
Accepted: 04 August 2016
Published: 18 August 2016
selective constraint that this feature is under.
Citation:
Cole LW (2016) The Evolution of ESTIMATING ORGANELLE NUMBER ACROSS THE EUKARYOTES
Per-cell Organelle Number.
Front. Cell Dev. Biol. 4:85. Organelles can be counted directly using molecular staining (Williamson and Fennell, 1979;
doi: 10.3389/fcell.2016.00085 Chazotte, 2011) and microscopy, but this is very labor intensive. Alternatively, organelles can

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Cole Evolution of Organelle Number

be quantified with some uncertainty through flow cytometry 1991) or even millions of mitochondria in an animal oocytes,
(Mattiasson, 2004), which has the drawback of underestimation as is the case in the oocytes of Xenopus laevis, which have
that results from the isolation process, or through the use been estimated to have on the order of 107 mitochondria
of biochemical probes (Robin and Wong, 1988). Recently, (Marinos, 1985). Mitochondria are very dynamic entities that
some have been using micro-dissection to estimate organelle are subject to frequent fusion and fission (Arimura et al., 2004a;
number by extrapolating counts from cross sections (Inuda and Kowald and Kirkwood, 2011) so this can change over time. Both
Wildermuth, 2004; Kubinova et al., 2014). Some would argue mitochondria (Gurdon et al., 2016) and chloroplasts (Thyssen
that the methods that involve direct counting are the only ones et al., 2012) have been shown to move between cells in plants,
appropriate to properly estimate the number of organelles in a even among those of different species, which may have some
cell, but they are impractical when it comes to some cases, such effect on per-cell counts of organelles. Some unicellular algae
as animal cells, that have thousands of mitochondria. will tend to have a single chloroplast (Itoh et al., 1996) whereas
These techniques are useful for low error quantification of some cells from plants, such as mesophyll cells, have been seen
organelle number within a cell but, with the advent of sequencing to have an average of ∼50 chloroplasts at their earliest stages
technology, one can use organelle genome copy number to of development (Boffey and Leech, 1982) and up to hundreds
estimate organelle number (Moraes, 2001). This, of course, comes of chloroplasts (Moller, 2004) with an average of 155 at their
with the consideration that there tends to be between 1 and latest stages of development (Boffey and Leech, 1982). Similarly,
10 copies of mtDNA per mitochondrion in animals (Satoh and mitochondria number has been shown to fall 25–50% during leaf
Kuroiwa, 1991; Weisner et al., 1992; Bereiter-Hahn and Voth, senescence in Vitis vinifera (Ruberti et al., 2014). These numbers
1996; Iborra et al., 2004; Legros et al., 2004; Brown et al., 2011; suggest that those early eukaryotes had one or a few of these
Kukat et al., 2011), between 50 and 200 copies of mtDNA in organelles, as in some modern unicellular eukaryotes, and then
yeast (Williamson and Fennell, 1979; Azpiroz and Butow, 1993; underwent an increase followed by a diversification in organelle
Solieri, 2010), and between 0 and 2 copies of mtDNA in plants number, resulting in the variation in organelle number we see
(Suyama and Bonner, 1966; Bendich and Gauriloff, 1984; Preuten among multicellular eukaryotes.
et al., 2010), though this estimate may be influenced by the These numbers not only vary significantly across organisms,
presence of substoichiometric mtDNA molecules (Palmer and but among tissue types. For example, there are more chloroplasts
Shields, 1984; Preuten et al., 2010; Mower et al., 2012), and up in leaf tissue than in other tissue (Li et al., 2001). Moist, leafy
to ∼1000 copies of cpDNA per mature chloroplast (Boffey and tissue in plants has been shown to have more mitochondria than
Leech, 1982). These per-organelle genome copy numbers can woody and stem tissue (Moller, 2004). This is the result of leafy,
also vary temporally; they can either change over the life span green tissue being the important focal tissue of photosynthesis.
of the organelle as is the case with most chloroplasts (Lamppa Mesophyll and stomata cells have also been shown to lose
et al., 1980; Scott and Possingham, 1980, 1983; Baumgartner et al., mitochondria at different rates during leaf senescence (Ruberti
1989; Kuroiwa, 1991), the lifespan of the organism as is the case et al., 2014). Studies of the mouse have shown that tissue of
with some mitochondria (Hartmann et al., 2011) and chloroplasts the liver, kidney, heart, and brain have different numbers of
(Zoschke et al., 2007), or change erratically and unpredictably mitochondria per-cell (Veltri et al., 1990). Organelle number
due to the unequal redistribution of nucleoid material between also varies in in terms of lability across tissue types. For
organelles during fusion and fission, which has been shown to be example, muscle cells are known to vary greatly in mitochondrial
the case in some mitochondria (Arimura et al., 2004a). content with organismal physical activity (Holloszy, 1967). The
A major caveat with these methods of quantification is that differences in mitochondria number among tissue types may be
they tend to estimate organelle number at a particular time point the result of varying energetic constraints (Holloszy, 1967; Veltri
or over a very small time range, while it is known that the number et al., 1990). It has also been shown that there can be large
of organelles is a very labile trait that can vary a great deal over reductions in chloroplast number in stressful high and low light
time (Stoecker and Silver, 1990; Arimura et al., 2004a). conditions in a variety of green plants (Higa and Wada, 2016).
Like many unicellular eukaryotes, which can have as few as a The extent to which per-cell mitochondria number varies
single mitochondrion or a few dozen mitochondria per-cell (Gray within tissue is largely unknown. Many methods used to
et al., 2004) and can also have on the order of 105 mitochondria count mitochondria within multicellular eukaryotes involve large
(Okie et al., 2016), multicellular eukaryotes tend to have a samples of tissue with flow cytometry or other methods that
wide range of per-cell mitochondria numbers with estimates in represent an aggregate of many cells within a tissue (Mattiasson,
mammalian somatic cells ranging from ∼80 to ∼2000 (Robin 2004). In vivo estimates would require microscopy of many cells
and Wong, 1988; Bogenhagen, 2011; Kukat et al., 2011) and within the same tissue of the same organism. Variability has been
from ∼200 to ∼600 in plant mesophyll cells (Logan, 2007). assessed within a HeLa cell line, which was shown to contain
Yeast have been shown to vary in terms of per-cell mitochondria between 383 and 882 mitochondria per-cell (Posakony et al.,
number based on substrate despite relatively consistent per-cell 1977), though this is mostly the result of differences in cell cycle
mtDNA copy number—for example, yeast grown on a glucose stages. Furthermore, this should not be interpreted as a reflection
substrate were shown to contain 2–3 mitochondria that are of natural or in vivo variation of within-tissue organelle number.
branched in structure while those grown on an ethanol substrate Within-tissue variation in chloroplast number, however, has been
contain 20–30 tubular-shaped mitochondria (Visser et al., 1995). shown to be rather extensive with between ∼2 and ∼140 fold
Occasionally, there can be tens of thousands (Satoh and Kuroiwa, variation in chloroplast number in palisade tissue from different

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Cole Evolution of Organelle Number

green plants (Higa and Wada, 2016). To what extent and how that interact with organelle-encoded proteins (van Wijk, 2004;
within-tissue per-cell organelle number variation is maintained Giegé et al., 2005; van Wijk and Baginsky, 2011) and (2)
will require more data and this will serve as a prerequisite to those that encode proteins in the organelle genomes themselves,
analyses with methods from quantitative genetics, developmental especially those that interact with nuclear proteins, whose
biology, and physiology. potential importance will be explained later in the essay. The
three compartments in which these genes reside present different
population genetic environments that presumably play a large
ORGANELLE BIOGENESIS
role in dictating the relative power of selection in the evolution
At the molecular level, per-cell organelle number is underpinned of organelle number.
by series of transcriptional pathways. These processes are distinct Population mutation rate (often represented by π or θ),
but involve related components in chloroplasts and mitochondria which is a reflection of the population genetic environment as
that mostly control the pattern of division of organelles and the influenced by mutation and drift, is 2N g u where u is the mutation
replication and transcription of their genomes. An understanding rate per nucleotide per generation and N g is the effective number
of what genes are involved in organelle biogenesis is necessary to of genes at a locus (Lynch, 2006). For diploid nuclear genomes,
fully understand the evolution of organelle number in cells. this term is equal to 4N e u where N e is the effective population
The so-called “master regulators” of mitochondrial biogenesis size. This is important to consider as genes that dictate organelle
are members of the PGC (peroxisome proliferator-activated number, like those that regulate mitochondrial biogenesis such
receptor-γ) family of co-transcriptional regulatory factors as the PGC family (Ventura-Clapier et al., 2008) and those that
(Irrcher et al., 2003; Ventura-Clapier et al., 2008). In particular, encode the dynamin-like proteins and Fis-type proteins that are
PGC-1α is known to activate different transcription factors that involved in plastid and mitochondrial division (Gao et al., 2003;
interact with Tfam (mitochondrial transcription factor A), which Arimura et al., 2004b; Lu et al., 2011), are encoded in the nucleus.
is involved in the replication and transcription of mtDNA and The argument has been made that, due to the haploidy
the transcription of nuclear-encoded mitochondrial components and maternal transmission of organelles, population mutation
(Virbasius and Scarpulla, 1994). Though the connection between rate is simply equal to N e u in organelle genomes (Palumbi
PGC-1α and the physical division of mitochondria is not fully et al., 2001). Alternatively, it has been argued that this idea
understood, it has been shown to increase respiration in cells (Wu assumes an incorrect parity of selection and recombination
et al., 1999). The division of mitochondria is known to involve between nuclear and organelle genomes and equivalency between
the dynamin-like proteins (Arimura et al., 2004b) and Fis-type males and females with respect to progeny (Lynch et al., 2006).
proteins (Lu et al., 2011). These pathways are mostly understood Furthermore, organelle mutation rate is thought to vary much
from the perspective of human and mouse mitochondria, so these between different taxa. For example, when compared to nuclear
processes may be quite different in the mitochondria of other genomes, animal mitochondrial mutation rates appear to be
eukaryotes. much higher (Brown et al., 1979) and plant mitochondrial
Plastid biogenesis is much less well-understood than mutation rates appear to be much lower (Palmer and Herbon,
mitochondrial biogenesis because many factors implicated in 1988).
this process are often only known from the phenotyping of Regardless of any of these considerations, the effective
Arabidopsis mutants (López-Juez, 2007). Those factors whose population size is generally thought to be smaller in organelle
functions are well-understood seem to mostly be involved in genomes (Palumbi et al., 2001; Lynch et al., 2006) and, as such,
the formation of plastid division rings including dynamin-like the strength of drift is thought to be greater than that of the
proteins (Gao et al., 2003), like those involved in mitochondrial nucleus, but the efficacy of selection could be just as great
biogenesis. As such, the process of plastid division is mostly (Cooper et al., 2015) and vary greatly between different taxa
understood to be a mechanical one with daughter plastid with different mutation (Brown et al., 1979; Palmer and Herbon,
components mostly being the result of random, unequal 1988) and recombination regimes (Rokas et al., 2003; McCauley,
segregation of the contents of the parent cell (López-Juez, 2007), 2013). As a result of these differences, for example, if organelle-
though some components of the plastid, such as thykaloids, seem encoded genes are important in the determination of per-cell
to have an equitable redistribution between daughter plastids as organelle number, the efficacy of selection on organelle number
regulated through the ARTEMIS and PEND proteins (Fulgosi may be more so in animals than in plants because of the greater
et al., 2002; Terasawa and Sato, 2005). mutation rate (Brown et al., 1979; Palmer and Herbon, 1988) and
lower incidence of recombination (McCauley, 2013) in animal
mitochondrial genomes.
THE POPULATION GENETIC
ENVIRONMENT OF GENES INVOLVED IN
ORGANELLE NUMBER METABOLISM AS A POTENTIAL
SELECTIVE CONSTRAINT
The genes involved in determining organelle number mostly
fall within one of two categories: (1) those that are in the The metabolic needs of a cell and the capacity for organelles to
nuclear genome, including those that control the division of fulfill these needs may act as selective constraints on the number
organelles and the over two-hundred genes that encode products of organelles in a cell. Mitochondria, for example, perform a

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Cole Evolution of Organelle Number

few different metabolic processes, such as the production of some semblance of physiological homeostasis at both the cellular
ATP through primarily aerobic respiration, regulation of cellular and organismal levels.
metabolic processes (McBride et al., 2006), and steroid synthesis Many mitochondrial encoded proteins (Giegé et al., 2005) and
(Rossier, 2006). Chloroplasts perform photosynthesis, producing almost all plastid encoded proteins (van Wijk, 2004; van Wijk
NADPH and ATP through light reactions and glucose through and Baginsky, 2011) form multi-subunit complexes with nuclear
the Calvin cycle, and are also involved in fatty acid (Rawsthorne, encoded products, of which there are about two-hundred.
2002) and amino acid synthesis (Burgess, 1989). Among these complexes are ribosomes and ATP synthases of
Metabolic needs have been thought to drive the relationship both organelles. Rubisco, PEP, and the major photosynthetic
between the total amount of mitochondria and body mass across complexes of the plastid and all four major complexes of the
organisms according to a power law (Kleiber, 1947). Per-cell electron transport chain in the mitochondrion are also among
mitochondria content is also seen to change with cell size across those formed by complexing with nuclear subunits. These are
the cell cycle (Posakony et al., 1977). Single-celled eukaryotes formed from specific stoichiometric ratios of subunits. The
do not appear to follow Kleiber’s power law for mitochondria number of organelles could play a significant role in influencing
or chloroplasts, but do appear to follow linear and sublinear the number of these products produced in a cell and, as such, the
scaling, respectively, for organelle number with cell size (Okie nuclear-organelle subunit stoichiometry could act as a significant
et al., 2016). This study also shows that organelle size does not constraint on the number of organelles in the cell.
appear to scale strongly with cell size in single-celled eukaryotes, Though levels of transcription do differ between genes,
suggesting that per-cell organelle number is more important than mitochondrial transcription in animals is mostly performed at
organelle size as a means of modulating energetic requirements a constitutive level (Bendich, 1988) because it occurs over the
at the scale of the cell. Rafelski et al. (2012), however, did note entire circular mitochondrial genome, one strand at a time
a sublinear, positive correlation between cell volume and total (Lee and Clayton, 1998). This constitutive transcription and
organelle volume in yeast. Given the relationship between cell the tenuous connection between metabolic activity and gene
size and per-cell mitochondrial content, perhaps there is an expression in mitochondrial genomes (Bendich, 1988) suggest
optimal per-cell mitochondria number given cell size and the that, in order to maintain the appropriate numbers of transcripts,
nature of mitochondrial biogenesis. other means at other levels must be utilized by the cell. Another
It may soon be possible to obtain an estimate of whole-cell potential means of controlling gene product stoichiometry may
energetic requirements per unit time and use this to determine be by adjusting organelle DNA copy number per organelle, but
the optimal per-cell mitochondrial content to further understand it has been shown that, since this quantity varies so little (Boffey
the role of selection on this trait through quantitative genetics. and Leech, 1982; Weisner et al., 1992), per-cell organelle number
Though it is not yet possible to completely understand the rather than per-organelle DNA copy number is the major driver
energetic needs per unit time in a eukaryotic cell, there has been of per-cell organelle DNA copy number (Robin and Wong, 1988;
some progress in developing theoretical models that can estimate Zoschke et al., 2007). Adjusting the number of organelles could
the metabolic and energetic needs of a single cell (Suthers et al., act as a broad-scale blunt means of regulation for these genes,
2009; Karr et al., 2012; Lynch and Marinov, 2016). as an alternative to regulating expression on a gene-by-gene or
genome-by-genome basis. As such, per-cell organelle number
could play an important role in maintaining the stoichiometry
COORDINATION BETWEEN THE NUCLEUS between nuclear- and organelle-encoded subunits.
AND ORGANELLES: TRANSCRIPTION AND Given a particular cell, there could be an optimal number
TRANSLATION of organelles to maintain the stoichiometry between nuclear
and organelle gene products. Counting gene products can be
Since the original endosymbiosis events, there has been a performed at the level of transcription by looking at the number
substantial integration of the function of organelles and their of particular mRNAs in a cell (Itzkovitz et al., 2012) or at the level
hosts, some of which is due to the transfer of genes from of translation by counting the number of particular proteins in a
organelle to nuclear genomic compartments over evolutionary cell (Huang et al., 2004). By doing this, we could see how closely
time (Blanchard and Schmidt, 1995). As a result, most protein these quantities track the expected stoichiometry in some cases.
products encoded in the organelles form complexes with those Since we can estimate the number of organelles in a cell by the
that are encoded in the nucleus. There have also evolved to methods stated earlier, it may be possible to survey many cells
be nuclear-encoded transcription factors (Leigh-Brown et al., of the same type for the density of organelles and see if there
2010) and proteins involved in post-transcriptional modification is an optimum that gives a ratio of gene products closest to the
such as RNA editing (Schmitz-Linneweber and Small, 2008) that expected stoichiometric ratio.
regulate the expression of mitochondrial genes. As such, some If we can make the assumption that it is most fit for cells
level of stoichiometric balance has to be maintained between to produce the least amount of excess gene product for those
nuclear- and organelle-encoded factors during the processes of proteins that form obligatory complexes, looking at many cells
transcription and translation to ensure the proper allocation may be able to tell us which have the closest to the optimum
of resources and to prevent waste in terms of energy and per-cell organelle number. A comparison of the typical per-
macromolecules. Maintenance of proper stoichiometric ratios for cell organelle density to our best estimate of the optimum per-
gene products is necessary, at least to some degree, in maintaining cell organelle density may tell about the role of evolution in

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Cole Evolution of Organelle Number

shaping organelle number. For example, if most cells have a far- per-cell organelle number through selection will be more clear
from-optimal organelle number per-cell, it may merit further as the field of cell-scale proteomics becomes more empirically
investigation into the possibility of there being a drift barrier and computationally tractable. As these techniques become
(Lynch, 2011) or some other, previously not understood, physical increasingly practical, we will be able to apply the analytical
constraint that is preventing most cells from reaching this approaches of population and quantitative genetics to better
stoichiometric optimum. understand this issue from an evolutionary perspective.

CONCLUSION AUTHOR CONTRIBUTIONS

Metabolism and the production of organelle encoded gene The author confirms being the sole contributor of this work and
products are both important to consider in the context of approved it for publication.
organelle and cell evolution. Cells have energetic requirements
and need to maintain some semblance of particular gene product ACKNOWLEDGMENTS
quantities in order to function properly. Work in the fields
of biophysics and physiology will allow us to determine how I thank Mike Lynch for motivating the writing of this manuscript.
these processes are impacting fitness and constraining per-cell I also thank Jeff Palmer and Elizabeth Skippington for their
organelle number. To what extent these processes constrain discussions on organelles.

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doi: 10.1007/BF00873688 which does not comply with these terms.

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