Human Reproduction Update, Vol.21, No.5 pp. 671–689, 2015
Advanced Access publication on May 14, 2015 doi:10.1093/humupd/dmv024
Evolutionary defined role of the
mitochondrial DNA in fertility,
disease and ageing
Auke B.C. Otten 1,2 and Hubert J.M. Smeets 1,2,*
1
Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, PO box 616 (box 16), 6200 MD Maastricht,
The Netherlands 2School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht,
The Netherlands
*Correspondence address. E-mail: [email protected]
Submitted on October 6, 2014; resubmitted on February 5, 2015; accepted on April 22, 2015
table of contents
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Introduction
Search methods
Mitochondria: function, origin and evolution
Mitochondrial metabolism and OXPHOS
Evolution of mitochondria
Animal, plant and fungal mitochondrial genomes
Evolutionary mechanisms in mitochondria
Mutations in the mtDNA: Muller’s ratchet and mutational meltdown
Muller’s ratchet in mtDNA
Mitochondrial evolutionary mechanisms to balance high mutation loads
The role of mtDNA evolutionary mechanisms in fertility, disease and ageing
Human mitochondrial diseases
MtDNA disease manifestation and transmission
Fertility and viability
Human ageing
Concluding remarks
background: The endosymbiosis of an alpha-proteobacterium and a eubacterium a billion years ago paved the way for multicellularity and
enabled eukaryotes to flourish. The selective advantage for the host was the acquired ability to generate large amounts of intracellular hydrogendependent adenosine triphosphate. The price was increased reactive oxygen species (ROS) inside the eukaryotic cell, causing high mutation rates
of the mitochondrial DNA (mtDNA). According to the Muller’s ratchet theory, this accumulation of mutations in asexually transmitted mtDNA
would ultimately lead to reduced reproductive fitness and eventually extinction. However, mitochondria have persisted over the course of evolution, initially due to a rapid, extreme evolutionary reduction of the mtDNA content. After the phylogenetic divergence of eukaryotes into
animals, fungi and plants, differences in evolution of the mtDNA occurred with different adaptations for coping with the mutation burden
within these clades. As a result, mitochondrial evolutionary mechanisms have had a profound effect on human adaptation, fertility, healthy reproduction, mtDNA disease manifestation and transmission and ageing. An understanding of these mechanisms might elucidate novel approaches for
treatment and prevention of mtDNA disease.
methods: The scientific literature was investigated to determine how mtDNA evolved in animals, plants and fungi. Furthermore, the different
mechanisms of mtDNA inheritance and of balancing Muller’s ratchet in these species were summarized together with the consequences of these
mechanisms for human health and reproduction.
& The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Otten and Smeets
results: Animal, plant and fungal mtDNA have evolved differently. Animals have compact genomes, little recombination, a stable number of
genes and a high mtDNA copy number, whereas plants have larger genomes with variable gene counts, a low mtDNA copy number and many
recombination events. Fungal mtDNA is somewhere in between. In plants, the mtDNA mutation rate is kept low by effective ROS defence and
efficient recombination-mediated mtDNA repair. In animal mtDNA, these mechanisms are not or less well-developed and the detrimental mutagenesis events are controlled by a high mtDNA copy number in combination with a genetic bottleneck and purifying selection during transmission. The mtDNA mutation rates in animals are higher than in plants, which allow mobile animals to adapt more rapidly to various environmental
conditions in terms of energy production, whereas static plants do not have this need. Although at the level of the species, these mechanisms have
been extremely successful, they can have adverse effects for the individual, resulting, in humans, in severe or unpredictably segregating mtDNA
diseases, as well as fertility problems and unhealthy ageing.
conclusions: Understanding the forces and processes that underlie mtDNA evolution among different species increases our knowledge
on the detrimental consequences that individuals can have from these evolutionary end-points. Alternative outcomes in animals, fungi and plants
will lead to a better understanding of the inheritance of mtDNA disorders and mtDNA-related fertility problems. These will allow the development of options to ameliorate, cure and/or prevent mtDNA diseases and mtDNA-related fertility problems.
Key words: mitochondria / evolution / mitochondrial disease / reproduction / infertility
Introduction
Mitochondria are fundamental to the origin of (multicellular) eukaryotes
and provide the eukaryotes with the capability of generating energy, at
the cost of high mutagenesis, partially due to the production of reactive
oxygen species (ROS). It is this high mutation rate that has had a profound
impact on the composition and inheritance of the genetic material within
the mitochondria: the mitochondrial DNA (mtDNA). This mtDNA is indispensable for oxidative phosphorylation (OXPHOS), the process of
aerobic adenosine triphosphate (ATP) production in the mitochondria
as it encodes part of the OXPHOS proteins (Fig. 1). The remainder of
the mitochondrial proteins are encoded by the nucleus and are imported
into the mitochondria. The presence of ROS can lead to mutation rates
which, in combination with uniparental, asexual inheritance, would eventually have led to disappearance of the mtDNA according to Muller’s
ratchet, but obviously that has not occurred. Eukaryotes have developed
a variety of strategies to prevent fixation of mtDNA mutations. Although
beneficial at the level of the species, these evolutionary mechanisms can
have adverse effects at the level of the individual. The driving forces and
underlying mechanisms of mitochondrial evolution across eukaryotes
most likely explain how human mtDNA disease and mtDNA-related fertility problems arise and are being transmitted, and also reveal what
approaches could be undertaken for treatment and/or prevention.
Search methods
The scientific literature was searched using PubMed for studies associated with mtDNA evolution, mtDNA inheritance and mtDNA characteristics with a focus on animals, plants and fungi. This search resulted in
an overview on how mtDNA evolved from its origin to its current characteristics. These characteristics were used as novel search terms such as
ROS, Muller’s ratchet, mtDNA recombination, mtDNA inheritance,
mtDNA bottleneck and mtDNA purifying selection in relation to
mtDNA mutation rates. From these mechanisms, we studied the consequences that individuals suffer from these evolutionary mechanisms
by searching literature for mtDNA disease, mtDNA adaptation and
mtDNA and fertility. From these three separate searches, we elucidated
the relevant characteristics, evolutionary mechanisms and consequences
that the evolution of the mtDNA has on human health and fertility.
Mitochondria: function, origin
and evolution
Mitochondrial metabolism and OXPHOS
Mitochondria are powerhouses producing the majority of cellular energy
(ATP) inside the mitochondrial double membrane. The number of
mitochondria within a cell can vary depending on the energy demand
of the specific cell type. Although energy production is the main function
of mitochondria, other cellular processes, such as heme synthesis,
cellular apoptosis and calcium homeostasis, are also carried out by
mitochondria.
Aerobic generation of energy is a multistep process ending with
OXPHOS (Fig. 1). NADH and FADH2 drive the OXPHOS system
which is embedded in the mitochondrial inner-membrane and which
consists of five enzyme complexes (I –V) and two electron carriers:
co-enzyme Q and cytochrome c (Fig. 1). NADH and FADH2 donate
electrons to and thereby reduce complex I (NADH) or complex II
(FADH2) which are re-oxidized by the electron carrier co-enzyme
Q. The chain of oxidation and reduction events and electron transfer
is continued through complex III, electron carrier cytochrome c and
complex IV. The energy released during this process is used by
complex I, III and IV, but not II, to transport protons (H+) from the mitochondrial matrix into the inter-membrane space. Finally, these protons
flow back across the membrane through complex V, leading to the production of ATP out of ADP and inorganic phosphate (Pi). The ATP is
transported out of the mitochondrial matrix into the cytosol by the
adenine-nucleotide transporter (ANT1) (Neckelmann et al., 1987),
where it can be used as an energy source (Fig. 1). The process of
OXPHOS is well-conserved, especially the core subunits (Gabaldon
and Huynen, 2003, 2004), although some species lack complex I, e.g.
most yeast (Baile and Claypool, 2013).
Evolution of mitochondria
Originally, mitochondria were free-living prokaryotes but more than a
billion years ago an endosymbiotic event made the free-living bacterium
part of what became a eukaryotic cell (Lane and Martin, 2010). It is
unknown whether the symbiosis was immediately beneficial for the
host. According to a recent theory, the mitochondrion originated from
Evolutionary role of mtDNA in fertility and disease
673
Figure 1 ATP generation processes inside mitochondria and the production of ROS. Carbohydrates are broken down by glycolysis, resulting in ATP as
well as pyruvate, which can be transformed into acetyl-CoA. Fatty acids (FAs) are biochemically dissimilated by mitochondrial beta-oxidation, which also
results in acetyl-CoA. This acetyl-CoA is the substrate for the Krebs cycle, where the acetyl-group is donated to oxaloacetate, generating citric acid, which is
dissimilated stepwise during the Krebs cycle resulting in ATP generation and production of the reducing agent NADH. NADH is also produced during the
beta-oxidation along with FADH2, another reducing agent. These reducing agents drive the process of ATP production by OXPHOS. ROS are produced as
by-products of the OXPHOS and can damage the mtDNA.
an obligate intracellular bacterium that parasitized on the energetic capabilities of its host due to its moderate OXPHOS capacity (Wang and
Wu, 2014). However, during evolution mitochondria changed from
being a parasite into a central mutualistic organelle.
It has long been thought that the benefit for the anaerobic host, an amitochondrial eukaryote (or archezoan), was the acquired ability to detoxify oxygen (Embley, 2006); this hypothesis is known as the archezoan
theory (Koonin, 2010). However, the absence of amitochondrial eukaryotes (Embley and Hirt, 1998) and early phylogenetic studies suggest that
the archezoan theory is incorrect. Eukaryotic starlike-trees exist, composed of a few large hypothetical eukaryotic subgroups, each consisting
of primarily microbial eukaryotes that radiated at the same time (Keeling
et al., 2005). This fits with an alternative hypothesis, the symbiogenesis
theory (Koonin, 2010), which, although the mechanism of endosymbiosis is unclear, suggests a prokaryotic rather than a eukaryotic host.
Instead of detoxification of oxygen, hydrogen-dependent ATP production was the eventual fundamental force for the symbiotic association
between an anaerobic (hydrogen-dependent) archaebacterium (the
host) and a respiring, facultative anaerobic eubacterium (the symbiont)
that generated hydrogen as waste product (Martin and Muller, 1998).
The symbiogenesis theory is revolutionary, since it further implies that
eukaryotes evolved integral, instead of prior, to mitochondrial endosymbiosis, as was generally accepted within the archezoan theory. The symbiogenesis theory also explains the ubiquitous and diverse nature of
mitochondrial organelles (Embley, 2006; Hampl et al., 2008). The divergence of anaerobic mitochondria and mitochondria-related organelles,
in combination with the widely accepted view that the symbiotic event
occurred only once (since all known eukaryotic groups contain a preserved set of homologous genes in their mtDNA), can only be explained
if the mitochondrial host was of anaerobic prokaryotic origin (Embley,
2006).
Regardless of the founding theory, it is therefore without doubt
that the mitochondrion itself is of prokaryotic origin. Prokaryotes
lack a nucleus and organelles and their genetic material is soluble and
located in the volume created by the cell membrane. Although the
exact mitochondrial ancestor is unknown, a recent phylogenetic
study has assigned this proto-mitochondrion to the class of alphaproteobacteria (Ferla et al., 2013). Mitochondria are small compared
with their alpha-bacterial ancestors and the Rickettsia species seems
to be the closest relatives of mitochondria, with a genome of 1 Mb
(Table I), containing all the homologous genes needed for OXPHOS
(Muller and Martin, 1999).
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Otten and Smeets
Table I Sizes and gene count of some promitochondrial and mitochondrial genomes.
Genome
Size
(Potential)
genes
Specific remarks
Reference
.............................................................................................................................................................................................
a-proteobacteria
B. japonicum
nuclear
9.1 Mb
8317
M. loti
nuclear
7 Mb
6752
C. crescentus
nuclear
4 Mb
3767
R. prowazekii
nuclear
1 Mb
834
43% similar to M. Loti
Kaneko et al. (2002)
Kaneko et al. (2002)
Nierman et al. (2001)
All homologous genes for the ATP system
Andersson et al. (1998),
Muller and Martin (1999)
Largest known mt gene content
Lang et al. (1997)
Early eukaryotes (animal relatives)
R. americana
mt
69 034 bp
97
M. brevicollis
mt
76 568 bp
55
A. parasiticum
mt
0.3– 8.3 kb
53
Contains sets of mt chromosomes
Burger et al. (2003)
mt
13 764 bp
36
Lacks ATPase8 gene
Gabaldon and Huynen (2003)
Larger displacement loop (D-loop)
Roe et al. (1985)
Burger et al. (2003)
Animals
C. elegans
X. laevis
mt
17 553 bp
37
M. Musculus
mt
16 299 bp
37
Bayona-Bafaluy et al. (2003)
B. taurus
mt
16 338 bp
37
Anderson et al. (1982)
S. scrofa
mt
16 613 bp
37
Lin et al. (1999)
H. sapiens
mt
16 569 bp
37
Anderson et al. (1981)
O. tshawytscha
mt
16 644 bp
37
Wilhelm et al. (2003)
D. rerio
mt
16 569 bp
37
Broughton et al. (2001)
M. viride
mt
42 424 bp
65
A. thaliana
mt
366 924 bp
57
M. polymorpha
mt
186 400 bp
94
Cucurbitaceae sp.
mt
2400 kpb
P. anserina
mt
100 314 bp
81
Contains 16 introns
Cummings et al. (1990)
S. commune
mt
49 704 bp
49
Contains no introns, no repeat sequences
Specht et al. (1992)
S. cervisae
mt
85 779 bp
46
H. uvarum
mt
18 884 bp
33
Shortest fungal mitochondrial genome, linear
Pramateftaki et al. (2006)
C. alblicans
mt
40 420 bp
45
Almost no recombination
Anderson et al. (2001)
Plants
A green algae (before plant diversification)
Turmel et al. (2002)
Unseld et al. (1997)
Oda et al. (1992)
?
Ward et al. (1981)
Fungi
Animal, plant and fungal mitochondrial
genomes
The mitochondrial genomes of animals, plants and fungi (Table I) display a
strong reduction in gene number and genome size during evolution. Most
of these changes occurred between the bacterial ancestor and the Last
Eukaryotic Common Ancestor (LECA) and are the result of both
losses of alpha-proteobacterial genes, alongside with endosymbiotic
gene transfer (EGT) from the alpha-proteobacterial DNA to the
nucleus. The net result is that mainly genes encoding proteins involved
in energy metabolism and translation are maintained (Huynen et al.,
2013), at the expense of, for example, genes for repair and recombination of DNA. Although most of these changes occurred very early
during mitochondrial evolution, before the radiation of eukaryotes,
subtle proteome evolution still occurs (Huynen et al., 2013) and, basically, the mtDNA is unique for each species and tailored for its specific
nuclear background. As a result, mitochondria are not functional across
species (further discussed under ‘Human mitochondrial diseases’).
Foury et al. (1998)
The mtDNA has a genetic code, which differs from the genetic code
in the nucleus [NCBI: http://www.ncbi.nlm.nih.gov/Taxonomy/Utils/
wprintgc.cgi (5 May 2015, date last accessed)]. These differences arose
during evolution after endosymbiosis. For example, in metazoan mitochondria the UGA codon is allocated to Tryptophan, while it serves a
stop codon in the nucleus, indicating that this codon reassignment has
occurred within a common ancestor of Metazoa. Likewise, the AGN,
AUN and AAN codons changed during metazoan evolution. The characteristics of the transfer RNAs (tRNAs) restrict the manner in which
codes can change (Yokobori et al., 2001) and it seems that EGT continued until, although roughly estimated, the UGA codon was switched
from a stop codon to amino acid coding in the animal and fungal line
(Leblanc et al., 1997; de Grey, 2005). A number of proteins from alphaproteobacterial origin were lost and replaced by host proteins as part of
the process of non-orthologous gene displacement (Koonin et al., 1996),
giving some species special types of proteins that are absent in others,
depending on when and how the event occurred during evolution.
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Evolutionary role of mtDNA in fertility and disease
Crucial in the development of mitochondria as intracellular organelles
was the acquisition of a system to import proteins from the cytosol into
the mitochondria (Timmis et al., 2004). This system facilitated both expansion of the mitochondrial proteome and mtDNA genome reduction,
since nuclear-encoded proteins can be imported into the mitochondria
(Gabaldon and Huynen, 2004). Acquisition of the ATP/ADP transporter
to release mitochondrial-produced ATP into the cytosol gave the
mitochondria their crucial position as powerhouses (Amiri et al.,
2003). Together, gene loss, replacement, transfer and acquisition have
made modern mitochondria separate from their alpha-proteobacterial
ancestors.
Animals
Animal mitochondrial genomes have some important unique characteristics. First, the mtDNA underwent the most extensive genome reduction, resulting in a compact genome, ranging from 13 764 bp in
Caenorhabditis elegans to 17 553 bp in Xenopus laevis (Table I), with
only 14–16% of the proto-mitochondrial (alpha-bacterial) proteome
still present (Gabaldon and Huynen, 2003). Some structural OXPHOS
subunits and the necessary protein synthesis genes remained in the
mtDNA in higher animals, whereas the other genes were either transferred to the nucleus or lost due to the presence of genes with similar
function in the nuclear genome (Adams and Palmer, 2003). In almost
all animal species, including humans, the mtDNA contains only 37
genes, of which 13 are protein-coding genes, 2 encode ribosomal
RNAs (rRNA) and 22 encode tRNAs (Boore, 1999; Table I). Since
tRNAs cannot be imported from the cytosol into the mitochondria,
the tRNAs needed to translate the (different) genetic code are
encoded by the mtDNA itself (Yokobori et al., 2001). Secondly,
animal mitochondrial genomes contain no introns and few repeat
sequences (Boore, 1999). As a result, animal mtDNAs show only
limited signs of recombination (Barr et al., 2005). Thirdly, animals maintain a high mtDNA copy number (Table II). A cell can contain over
500–1000 mtDNA molecules, depending on the energy demand of a
cell (Smeets, 2013). In oocytes, the mtDNA copy number is highest,
ranging from 100 000 to 14 000 000 copies. A fourth feature of animal
mitochondrial genomes is its exclusive maternal inheritance, as sperm
mitochondria are actively degraded (Cummins, 1998) by proteasomal
(ubiquitin) and lysosomal (mitophagy) degradation pathways, during
which ubiquitin-binding receptors might serve as mitophagy receptors;
this mechanism is most likely prevalent among the animal taxa
(extensively reviewed in Sato and Sato, 2013; Song et al., 2014).
Finally, gene replacement and transfer have led to several genes being
unique to the animals (Metazoa) or to animals and fungi (Opisthokonta)
(see Table I from Huynen et al., 2013), an important one being the
nuclear-encoded DNA polymerase gamma genes (POLG and POLG2),
which have replaced the bacterial genes dnaN, dnaE en dnaQ. POLG is
the only polymerase found in mammalian mitochondria and is of viral
origin due to gene exchange (Filee et al., 2002).
Plants
Plant mitochondria differ from their animal counterparts in a number of
ways. First, genome reduction was less pronounced and more variable in
the plant mtDNA, which can contain over 100 genes (Unseld et al.,
1997). In addition, several genes that were transferred during animal evolution are retained in plant species, like the complex II genes sdh3 and
sdh4 (Unseld et al., 1997; Turmel et al., 2002). Especially the mtDNA
size of land plants differs from animal mtDNA, ranging, on average,
from 180 to 370 kb, with some extreme exceptions (Table I). Noncoding DNA was inserted in the mtDNA after the evolutionary branching of the land plants, since the common ancestor was gene-rich and
contained little introns (Turmel et al., 2003) and this resulted in the presence of repeated segments, introns, intronic Open Reading Frames and
incorporated foreign DNA of plastid, nuclear or plasmid origin (Unseld
et al., 1997; Bullerwell and Gray, 2004). With all these features, the
mtDNA genomes of plants resemble, unlike their animal counterparts,
the size-relaxed nature of a nuclear genome, including recombination
events, which give plants the ability to possess sub-genomic molecules
variable in size (Preuten et al., 2010). Therefore, no universal mtDNA
copy number exists in plants, but there are differential gene copy
numbers, as assessed by four mitochondrial genes that differ in their
copy number from each other and among tissues in the Arabidopsis
species (Preuten et al., 2010). Similar to animals, the predominant
mode of mitochondrial inheritance is maternal (Barr et al., 2005), governed by a variety of mechanisms, including methylation and/or zygotespecific gene expression (Sato and Sato, 2013).
Important for plants is the presence of another endosymbiont, the
chloroplasts. Its key function, photosynthesis, generates carbohydrates
and ATP from sunlight and water, which is the main energy source for
chloroplast-containing organisms, whereas mitochondria are the main
energy source (due to respiration) for organisms without chloroplast.
Mitochondria are still indispensable in plants for chloroplast function
Table II Features of the mitochondria and mtDNA in animals, fungi and land plants.
Animals
Fungi
Land plants
.............................................................................................................................................................................................
Compaction of mtDNA
+
+
2
Average number of genes
36–37
30– 80
50–100
Gene order conservation
+
2
+
mtDNA size (typical)
13–17 kb
20– 100 kb
180– 400 kb
Introns, repeat elements and recombination
2
+
+
Copy number
High
Intermediate?
Low
Type of inheritance
Maternal
Paternal, maternal and biparental
Maternal
Antioxidant system
+
+
+
676
and provide an alternative respiratory pathway for metabolic flexibility
during stress [e.g. high ROS, cold, drought (Atkin and Macherel,
2009)]. Alternative oxidase (AOX) in plant mitochondria is then
up-regulated, to circumvent complex III and IV of the OXPHOS, accepting carbons directly from the TCA cycle (Van Aken et al., 2009), thereby
reducing ROS damage. Furthermore, plants harbour two non-protonpumping NAD(P)H dehydrogenases, which are activated during stress
(Moller, 2001; Jacoby et al., 2012). Finally, in plants the nuclear-encoded
MSH1 gene is a unique property of the species, since it is the result of
the fusion between a bacterial DNA-repair homologue of MutS and
an endonuclease. It seems that this gene has enabled plants to have
recombination-mediated repair of the mtDNA (Abdelnoor et al.,
2006). As in animals, acquisition of genes can be restricted to the clade
of plants.
Fungi
Animal and plant mitochondria have been studied extensively, whereas
their fungal counterparts are much less-well described. Although fungi
are evolutionary more close to animals than plants, their mtDNA contains many plant characteristics. The presence of introns, which can be
up to 5 kb in length (Lang et al., 2007), explains the differential size
seen in fungal mtDNA, which ranges on average from 20 to 100 kb,
with some large exceptions (Table I). The appearance of repetitive elements in introns gives fungal mtDNAs their recombination capabilities
(Lang et al., 2007), which partly explains the enormous variation in
gene order among fungal mtDNAs (Lang et al., 2007; Aguileta et al.,
2014; Himmelstrand et al., 2014). It is not clear whether fungi have a
mtDNA copy number comparable to animals. However, since recombination is present, it is expected that their copy number can be regulated
in a similar fashion as in plants and that sub-genomic mtDNA molecules
will exist. Fungi are less complex eukaryotes with no strict energy
requirements and, although they contain no chloroplasts, fungi are not
as dependent on carbohydrates and lipids as animals. Instead, fungi
display a high degree of versatility in their metabolic demands and also
use different organic substrates, which can be as simple as nitrate or
ethanol. Fungi are scavengers and feed on nutrient molecules from
others and secrete digestive enzymes to the exterior to digest any nutrient that is available. The net result is that fungi are less dependent on
mitochondria than are animals, but more dependent than are plants
due to the absence of chloroplasts.
The mtDNA inheritance of fungal mitochondria is complex, with no
universal mechanism of inheritance, allowing both uniparental and biparental inheritance (Barr et al., 2005). In yeast, an almost equal contribution
of mitochondria from both parents contributes to the zygote (Birky,
1995). Some fungi have biparental inheritance of mitochondrial plasmids
(small extragenomic mtDNA molecules) that retain parental mtDNAs
(Yang and Griffiths, 1993). Fungal mitochondria are considered as somewhere in between the evolution of plant and animal mitochondria.
Summary
Although most mtDNA changes appear to have taken place before the
radiation of the eukaryotes, the evolutionary paths of mtDNA among the
main eukaryotic clades could not differ more (Table II). In the next part of
this review, we will focus on how these differences have evolved and what
the impact is on mitochondrial biology for humans in health and disease.
Otten and Smeets
Evolutionary mechanisms
in mitochondria
Mutations in the mtDNA: Muller’s ratchet
and mutational meltdown
Asexual populations accumulate detrimental mutations according to
Muller’s ratchet (Muller, 1964; Allen et al., 2009; Goyal et al., 2012),
because the accumulation is irreversible due to the absence of
mutation-recovering mechanisms, such as sexual reproduction and
recombination-mediated repair, eventually decreasing the fitness of a
population (Lynch, 1996, Lynch et al., 2006; Rand, 2008; Goyal et al.,
2012). Extensive modelling (Gessler, 1995) and laboratory experiments
provide evidence for the existence of Muller’s ratchet and its potential for
decreasing fitness by a mutational meltdown (Goyal et al., 2012). Muller’s
ratchet explains, for example, the high incidences of non-synonymous
mutations in Caenorhabditis briggsae (Howe and Denver, 2008) and the
degeneration of the neo-Y chromosome in Drosophila miranda (Kaiser
and Charlesworth, 2010). Such degeneration has also been discussed
for the mammalian Y chromosome (Bachtrog, 2008).
Muller’s ratchet in mtDNA
The mtDNA is an asexual population, being inherited maternally in animals
and plants, making this genome also prone to the detrimental consequences of Muller’s ratchet. Following the path of evolution, the endosymbiosis of the mitochondria allowed an increased level of cellular energy and
the expression of a substantially larger number of proteins in eukaryotes
than in prokaryotes (Lane and Martin, 2010; Gray, 2012). This increased
energy is produced by OXPHOS, during which electrons leak to O2 and
produce ROS, like superoxide (Brand, 2010). This ROS toxicity arose simultaneously with the symbiosis event and the integration of metabolic pathways even enhanced the ROS production, that originally served as a cellular
response at the outskirts of the (possibly parasitic) bacterium (Speijer,
2014), also observed during plant-pathogen interactions (de Gara et al.,
2003) and in infected HeLa cells (Boncompain et al., 2010). While unicellular eukaryotes have low energy consumption and subsequent less ROS
production, the symbiosis event and the development of multicellularity
brought the ROS-producing endosymbiont inside the eukaryotic cells,
exposing the newborn eukaryotic (multicellular) organisms to a high and
detrimental ROS-induced mutagenesis level. This increased mutation
pressure, in combination with the limited action of recombination, e.g.
in mice (Hagstrom et al., 2014) and humans (Elson et al., 2001a), implies
an increased vulnerability of mtDNA to a mutational meltdown. Indeed,
in mammals, the mutation rate in mitochondria is much higher than
in the (recombining) nucleus (Lynch et al., 2006). Muller’s ratchet in
mitochondria has been quantified (Loewe, 2006) and molecular proof
exists for the process in mitochondrial tRNAs, which accumulate
mutations more rapidly compared with their nuclear counterparts
(Lynch, 1996).
If Muller’s ratchet could not be counteracted, the inevitable consequence of its genomic decay is extinction of species. However,
mtDNA and eukaryotes are still present today, suggesting solutions for
preventing detrimental mutation accumulation and subsequent declines
in reproductive fitness, which, in the context of mtDNA, are specific
mechanisms.
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Evolutionary role of mtDNA in fertility and disease
Mitochondrial evolutionary mechanisms
to balance high mutation loads
One of the parameters determining the rate of mutation-related decline
in fitness is the rate at which these mutations are introduced. In animals,
this mutation rate is much higher (up to 100× in mammals) compared
with that in plants. In mammalian mitochondria, the mutation rate is
25× higher than in the nucleus, whereas in plants this difference is
much lower (Lynch et al., 2006). Fungal mutation rates are more
similar to plants. A higher mutation rate in the mtDNA in animals
might reflect a higher adaptive capacity to balance mitochondrial
energy and heat requirements with respect to the environment
(Wallace, 2007). Plants lack this adaptive need, since they typically live
in restricted ecological niches, can rely on both mitochondria and chloroplasts for their energetic needs and they can survive as seeds, which
animals cannot. Fungi share this feature of plants by the production of
spores and are also less dependent on mitochondria due to their metabolic versatility. A higher mutational rate will generate mutations of any
type, meaning that higher adaptive capacities are at the cost of a higher
detrimental mutation load and a higher risk for mutation accumulation.
Several mechanisms have evolved to prohibit mutation accumulation:
mutation prevention, diluting the chance of acquiring mutations and recovery of mutations (Table III). Where EGT was an effective general
mechanism to lower mutation accumulative effects, species-specific
mechanisms also exist, underlying differences in mutation rates, as well
as differences in the mtDNA composition among species.
Mutation prevention: EGT and antioxidants
As mentioned above, a general way to avoid mutation accumulation is
moving the mtDNA genes to the nucleus, which is achieved by EGT,
which had already occurred in the LECA. Changes in the mtDNA
genome from this point resulted in the specific characteristics of
modern mitochondria in different species. The early evolutionary
pressure was likely to be very high, since EGT occurred at high rates
in all eukaryotic species (Blanchard and Lynch, 2000), despite being
very complex and involving, for example, acquisition of a transitpeptide to re-access the mitochondrion. This is corroborated by the
fission of several mitochondrial proteins, indicating that even the transfer of only a small part of a gene is favoured, as illustrated for the hydrophilic c-terminal portion of cytochrome c oxidase subunit 1 gene
(COX1; a subunit of complex IV) (Gawryluk and Gray, 2010). It is
conceivable that gene redundancy together with mitochondrial ROSmediated high mutation rates drives EGT. Since the nucleus is less
prone to mutations, because of its protection by histones and extensive repair and recombination, EGT is a successful tool to reduce mutation loads. The higher degree of EGT observed in animals, might
therefore be a reflection of the higher mutation rate of animal mitochondria. However, EGT was not completed and mtDNA has
remained in all species, most likely for biochemical reasons (the combination of extreme hydrophobicity of the mtDNA-encoded proteins,
precluded easy import in the mitochondria) and the introduction of
differences in the genetic code (as with the UGA codon) (de Grey,
2005). Mutation accumulation risk might not be the only evolutionary
force that contributed to EGT. Selection of small organellar genomes
might also be involved, having a replicative advantage, as the mtDNA
size is linked to the time and energy needed to complete mitochondrial
duplication (Berg and Kurland, 2000), and the level of metabolic
efficiency (Selosse et al., 2001).
The evolutionary role of ROS is obvious from the evolvement of
additional eukaryotic mitochondrial capabilities to mitigate the disadvantages of ROS production. These include (1) the peroxisomal breakdown
of fatty acids (FAs) which normally render a lot of ROS, (2) the uncoupling
of protons without the formation of ATP and ROS, (3) a shuttle that
ensures high concentrations of the antioxidant carnitine and (4) the
breakdown of dysfunctional ROS-producing mitochondria by mitophagy-mediated mitochondrial quality control (Kurihara et al., 2012;
Speijer, 2014; Speijer et al., 2014). Mutation rates introduced by ROS
can be further lowered by the presence of antioxidants. Especially in
plants and fungi, these systems, such as the AOX-system during stress
conditions in plants, are up-regulated so that they scavenge most of
the ROS that is produced.
Diluting the target: high copy number or introduction of non-coding
DNA
Plants and fungi have incorporated stretches of DNA that allow
recombination-mediated mtDNA repair (a feature that is almost absent
in animals) so protein-coding parts are less likely affected. Animals
achieve this by maintaining a multi-copy genome (typically . 500
copies/animal cell). A high copy number ensures that not all genes can
be affected by a mutation at the same time, leaving fully functional sets
of proteins always present. Mammalian mtDNA copy numbers are
highest in oocytes, typically above 100 000 copies, but vary among
Table III Species-specific mechanism to prevent mutation accumulation following Muller’s ratchet.
Prevention of mutations
EGT
Species-specific mechanisms
Animals
.............................................................................................................................................
(Land) plants
Fungi
.............................................................................................................................................................................................
Prevention of mutations
† Antioxidants (only limited)
† Highly developed antioxidants
† Chloroplast dependency
† Moderate antioxidants
† Metabolic diversity
Dilution of mutational chance
† mtDNA copy number
combined with a small genome
† Large genomes with introns
† Large genome with introns
Recovery of mutations
† mtDNA bottleneck
† Purifying selection
† Uptake of elements to allow
recombination and mtDNA
repair
† Uptake of elements to allow
recombination and mtDNA repair
† Bottleneck
† Somatic fusion
678
Otten and Smeets
different animal species (Table IV). There seem to be three classes: in the
first class, represented by humans, mice and rats, oocytes can have an
mtDNA copy number between 100 000 and 200 000 copies, although
some outliers are found. Secondly, for example in bovines, sheep and
pigs, the mtDNA counts of oocytes are typically above 300 000, but
below 1 000 000 copies. The final class, represented by salmon and zebrafish, have the highest mtDNA copy numbers of several million genomes.
An explanation for this variation might be the different implantation
patterns among the species or even the lack of implantation. Implantation
Table IV mtDNA copy numbers in oocytes among
different animal species.
Species
Median
Copy number
oocytes
Reference
........................................................................................
H. Sapiens
M. Musculus
R. Novegicus
256 000 143 000
Duran et al. (2011)
163 698
Santos et al. (2006)
193 000
Reynier et al. (2001)
256 000
May-Panloup et al.
(2005a)
384 251
Monnot et al. (2013)
598 350
Chan et al. (2005)
697 176
Murakoshi et al. (2013)
243 500 131 990
157 000
Cao et al. (2007)
175 000
Wai et al. (2008)
238 000
Wang et al. (2009)
249 000
Cree et al. (2008)
269 386
Thundathil et al. (2005)
430 000
Ou et al. (2012)
430 000
Zhang et al. (2011)
128 800 110 000
147 600
S. scrofa
B. taurus
246 984 138 022
O. tshawytscha
D. rerio
Zeng et al. (2009)
Kameyama et al. (2007)
El Shourbagy et al.
(2006)
145 368 –161 787
Gil et al. (2012)
239 392 –275 132
Mao et al. (2012)
246 984
Pawlak et al. (2011)
285 000
Sato et al. (2014)
323 038 –503 263
Spikings et al. (2007)
347 023
Santos et al. (2013)
367 057 134 896 –204 173
260 000
O. aries
Ge et al. (2012)
Jiao et al. (2007)
Michaels et al. (1982)
361 113
Hua et al. (2007)
373 000
May-Panloup et al.
(2005b)
385 332
Takeo et al. (2014)
807 794
Iwata et al. (2011)
744 633 744 633
3 200 000 3 200 000
Cotterill et al. (2013)
Wolff et al. (2011)
13 185 000 12 370 000
Otten (in preparation)
14 000 000
Zampolla et al. (2011)
has been classified into three categories: centric, eccentric and interstitial
(Wimsatt, 1975), based on the different types of interactions between
blastocysts and uterine cells. Centric implantation is characterized by a
large expansion of the blastocyst before implantation, followed by
fusion with the luminal epithelium (Lee and DeMayo, 2004). Bovines,
sheep and pigs have this type of implantation. Mice and rats, on the
other hand, have an eccentric implantation pattern, where the luminal
epithelium forms an invagination to surround the trophoblast. The
human implantation pattern is interstitial as the trophoblast passes
through the luminal epithelium to invade the endometrial stromal
and become imbedded into the wall of the uterus (Wimsatt, 1975).
A fourth group consisting of, for example, salmon and zebrafish, has
no implantation at all. Another factor can be the speed at which implantation occurs. Rats, mice and humans have an immediate, fast implantation, with immediate access to high levels of nutrients within the
female reproductive tract that can be utilized by the embryo (Leese,
2002), whereas at the other end of the spectrum, as in salmon and zebrafish, implantation is absent. The class with bovines, sheep and pigs is in
between with a more delayed implantation. A high copy number in
oocytes is needed to distribute mtDNA molecules over the daughter
cells in the absence of mtDNA replication during early embryogenesis
(May-Panloup et al., 2005b; Thundathil et al., 2005) and the differences
in copy number between species could be, although speculative, a reflection of different energetic needs during early development in animals.
These energy needs range depending on whether there is a rapid
direct access to the maternal blood supply, as in humans (lowest
mtDNA copy number), delayed access (intermediate mtDNA copy
number) or a complete dependence on their own energy storage from
the yolk-sac during the whole of embryogenesis (Wolff and Gemmell,
2008), as in fish (highest mtDNA copy number). The longer implantation
is delayed, the higher the energy demand is for the preimplantation
embryo, being most extreme when implantation is completely absent
(as in most cold-blooded species).
Mutation recovery: recombination-mediated repair
The last class of evolutionary mechanisms aims to remove or repair
mtDNA mutations. For this, plant mtDNA undergoes recombination,
mediated by repeat sequences, whereas animal mtDNA does not or
has only limited recombination. Repeat sequences cause ectopic recombination, a potential harmful feature that can disrupt coding frames and
gene expression, generating an additional selective pressure for efficient
mtDNA repair. For this repair, plants harbour a unique fusion-product:
the nuclear-encoded MSH1 gene (Abdelnoor et al., 2006). In Arabidopsis,
the MSH1 gene allows plants to have an efficient recombinationmediated mismatch repair and gene conversion, which reduces heteroplasmy (Davila et al., 2011) and is driven by the presence of repeat
sequences (Galtier, 2011). Fungal MSH1 genes are homologues of the
MutS gene, but do not possess the endonuclease domain and have
been reported not to be involved in mismatch repair in yeast (Sia and
Kirkpatrick, 2005). Although fungi display recombination due to accumulated repeats and introns, resulting in a high variability in the mitochondrial gene order, their mutation rate is intermediate between animals
and plants (Lynch et al., 2006; Aguileta et al., 2014). Recombinationmediated mtDNA repair in plants and some fungi can also occur via
other mechanisms (see Ricchetti et al., 1999) and is a perfect tool for
lowering the ROS-generated mutational burden (further discussed in:
Marechal and Brisson, 2010; Christensen, 2013).
679
Evolutionary role of mtDNA in fertility and disease
Mutation recovery: the mtDNA bottleneck
During the cleavage stages of embryogenesis, the total amount of
mtDNA is constant, indicating a random partitioning of the mtDNA
over the different daughter cells (Cao et al., 2007; Cree et al., 2008)
and only those cells that develop into an embryo will contribute to the
mtDNA pool of the newborn embryo, leading to a strong numerical
bottleneck (Bergstrom and Pritchard, 1998). In 1989, such a bottleneck
for mtDNA inheritance was first observed in Holstein cows, resulting in
rapid fixation of heteroplasmic variants during transmission to following
generations and a return to homoplasmy (Ashley et al., 1989); this implies
a sampling effect of mtDNA molecules early during embryogenesis. A restriction in the number of mtDNA molecules to be transmitted to the
next generation is followed by a strong amplification of these founder
molecules. During oogenesis in mice, a 100-fold increase in the mtDNA
amount has been observed, without any further increase during preimplantation development (Piko and Taylor, 1987). The sampling effect
and random genetic drift, during the formation of primordial germ cells
(PGCs) and oocyte maturation (clonal expansion) determine the
mtDNA that is inherited. The net result is a reset to homoplasmy
within a very short time-frame in which germ cell mtDNA is most sensitive to mutagenesis.
Besides the observations in mammals and rodents, the mtDNA
bottleneck has been described in Chinook salmon (Wolff et al., 2011)
and Danio rerio (Otten et al., in preparation). These two teleost species
are non-mammalian vertebrates and both show an mtDNA bottleneck
that is remarkably similar to the one documented in mice. This indicates
that, within the clade of Metazoa or at least the Vertebrata, the mtDNA
bottleneck is a highly conserved mechanism. The mtDNA copy number
is brought back to 200 in germ cells, which seems quite conserved
in humans, mice (Cree et al., 2008; Wai et al., 2008), salmon (Wolff
et al., 2011) and zebrafish (Otten et al., in preparation). Apparently,
this amount of mtDNA protects the species from pre-existing mutation
accumulation due to rapid segregation (Guo et al., 2013), while preserving fertility, resulting in a low vulnerability for de novo mutations to reach
significant heteroplasmy levels (as discussed below).
mtDNA count in the PGCs. Most likely, this is a prerequisite to selectively
filter out deleterious mtDNA mutations, since it is only when the
mtDNA load is small, that differences in organelle fitness can manifest
quickly and be selected for (Wai et al., 2010). Another possible mechanism of purifying selection has been postulated for Drosophila melanogaster
(Ma et al., 2014), based on selective replication of wild-type mtDNA
molecules with a more robust OXPHOS capacity; this hypothesis is
enforced by the observation that selective replication of functional
mtDNA molecules is able to restrict the transmission of deleterious
mtDNA variants and that the replicative advantage is coupled to mitochondrial fitness (Hill et al., 2014). The exact nature of this replicative advantage is not known, but could be achieved by the energy demanding
burst of mtDNA replication during oogenesis, allowing selection for
mtDNA with an efficient energy production, thus favouring their replication. Finally, mtDNA correction based on fusion and fission of mitochondria could be implicated in purifying selection, leading to selective
breakdown (mitophagy) of damaged mitochondria (Twig et al., 2008);
this process is thought to be regulated by Parkin (Glauser et al., 2011).
However, purifying selection seems to occur independently of Parkin in
D. Melanogaster (Ma et al., 2014).
Summary
As shown in Table III and Fig. 2, animals, plants and fungi have, besides
EGT, different species-specific mechanisms to ensure mitochondrial sequence homoplasmy and to slow mutation accumulation. The need for
higher adaptive abilities enforced animals to allow higher mutation
rates, and the detrimental consequences are counteracted by the
mtDNA bottleneck and purifying selection. The result for the species
is an optimal balance between negative deleterious mutations and positive adaptive mutations. As the bottleneck affects reproductive fitness,
this is also a critical factor in this balance. The incorporation of repeat
elements in the mtDNA of plants has enabled efficient recombinationmediated mtDNA repair in plant mtDNA, which results in low mitochondrial mutation rates. Fungi are described to have bottlenecks and
restricted somatic fusions (Bastiaans et al., 2014), whereas they simultaneously possess recombination-mediated mtDNA repair mechanisms
(Aguileta et al., 2014).
Mutation recovery: bottleneck-mediated selection
Mutations that escape the mtDNA bottleneck can be filtered out by
purifying selection at the level of the organelle in animals during early embryonic development (Bergstrom and Pritchard, 1998; Stewart et al.,
2008a, b). Purifying selection can take place either by positive or negative
selection on mtDNA sequences and evidence exists for both processes
(Bazin et al., 2006; Meiklejohn et al., 2007). In the mutator mouse, mutations accumulate at random in the mtDNA and purifying selection has
been detected by the analysis of mutation distribution after backcrossing.
Potential deleterious mutations are strongly underrepresented, implying
selection against these mutations in the mammalian germ line (Stewart
et al., 2008a, b). Furthermore, in transmitochondrial mice, a severe
OXPHOS-affecting mutation is eliminated rapidly from the maternal
germ line (Fan et al., 2008), further proving the existence of purifying
selection. The exact mechanism of purifying selection at the level of
the organelle is unknown, but is thought to be achieved by functional
testing of mtDNA at the single organelle level, most likely near or at
the bottom of the bottleneck. A number of mechanisms have been proposed (Shoubridge and Wai, 2008). The absence of mtDNA replication
during early embryogenesis (Ebert et al., 1988) leads to a very low
The role of mtDNA evolutionary
mechanisms in fertility, disease
and ageing
The way mitochondrial systems have evolved in animals and humans can
have profound effects on healthy human reproduction. It affects the way
mitochondrial diseases manifest and segregate (Shoubridge, 2001;
Zeviani and Di Donato, 2004; Taylor and Turnbull, 2005) and it has consequences for mammalian fertility (Wai et al., 2010), ageing, drug treatment (Kujoth et al., 2007) and reproductive options for patients.
Human mitochondrial diseases
Incomplete EGT and nuclear gene replacements (de Grey, 2005) have
led to the existence of two genomes in a eukaryotic cell, and consequently to two genetically distinct types of mitochondrial diseases. Defects in
the genes which have been transferred to the nuclear DNA lead to Mendelian diseases (Shoubridge, 2001), for example, in genes that control the
stability of the mtDNA (such as POLG and Twinkle). Defects in the
680
Otten and Smeets
Figure 2 Mitochondrial evolution and eukaryogenesis. An early endosymbiosis between two prokaryotes led to the eukaryotes which have evolved
differently with regard to their mtDNA.
mtDNA genes (37, in mammals) cause maternally inherited or sporadic
mitochondrial diseases (at a frequency of 1 in 10 000 individuals; Chinnery et al., 2012) and over 500 mtDNA point mutations have been identified (Ruiz-Pesini et al., 2007). The bigenomic origin of mitochondrial
proteins complicates the genetic diagnostics of mitochondrial diseases,
which are clinically highly variable, and for which, in most cases, no
clear genotype-phenotype correlations exist. Genome-wide diagnostic
procedures, like mtDNA sequencing in combination with whole-exome
sequencing are currently taking the stage. Without a diagnosis based on a
confirmed genetic defect, genetic counselling is challenging, since the
prognosis and recurrence risks are unclear (Vento and Pappa, 2013).
An established genetic defect in either the mtDNA or in nuclear genes
has profound consequences for the prognosis and transmission of the
disorder and, consequently, for the reproductive choices that patients
or carriers have. Prenatal diagnosis (PND) is the preferred option for prevention of the transmission of nuclear mutations, but for mitochondrial
disorders caused by heteroplasmic mtDNA mutations, PND is often unreliable due to difficulty in predicting the clinical phenotype from the mutation load in chronic villus sampling or amniocytes. Two exceptions
exist. First, mothers of patients with a de novo mutation, which is fairly
common for mtDNA disorders (see below), have a very low recurrence
risk and PND can be offered for reassurance. Secondly, carriers of low
levels of mtDNA mutations that display skewing can be offered PND
as it is likely that the interpretation of the mutation load is unambiguous
(Poulton and Turnbull, 2000; Smeets, 2013). Current alternatives for
preventing the transmission of mtDNA disorders are oocyte donation
and preimplantation genetic diagnosis (PGD). During PGD, oocytes
are fertilized in vitro, biopsied at the blastomeric stage and only
embryos with mutation below the threshold of clinical expression are
transferred to the uterus (Sallevelt et al., 2013). For most mtDNA mutations, insufficient data exist to define a mutation-specific threshold, but
this has been overcome by a recent meta-analysis which showed a
95% or higher chance of being unaffected at a (muscle) mutant level of
18% or less, irrespective of the mutation (Hellebrekers et al., 2012; Sallevelt et al., 2013). This opens up PGD for all heteroplasmic mtDNA mutation carriers that produce oocytes with mutation loads below this
threshold. This is obviously not the case for homoplasmic mutations
and for carriers with a very high mutation load of non-skewing mutations.
A possible future reproductive option in mtDNA disorders is nuclear
genome transfer (NGT), a procedure where the nuclear genome from
an mtDNA mutation-harbouring zygote or oocyte is transferred to an
enucleated acceptor harbouring mutation-free mtDNA (Craven et al.,
2010). This would be a solution for all mtDNA mutations, including
the homoplasmic mutations. As a result, the offspring would be, apart
from some carry-over, mtDNA mutation-free, while still harbouring
the nuclear DNA from the mother. However, many technical, ethical
681
Evolutionary role of mtDNA in fertility and disease
and safety issues need to be addressed and settled, before NGT can be
applied in clinic [see also (Craven et al., 2011; Smeets, 2013)].
One aspect in this debate concerns the withdrawal of the mtDNA
from its natural nuclear counterpart. It is a consequence of the two obligate genomes that OXPHOS integrity is governed by mitonuclear interactions and both genomes should match perfectly, requiring fast and
efficient adaptations when variations arise in one of the genomes
(Wolff et al., 2014). The high mutation rates in the mtDNA force
counter-adaptations in the nuclear genome that restore deleterious mutation consequences, as an evolutionary rescue (Dowling et al., 2008).
A certain level of mitonuclear variation is acceptable within populations,
most likely to allow a certain degree of adaptation to environmental
changes and allows long-term sustainability of our biodiversity when environmental circumstances change, creating new selection pressures
(Wolff et al., 2014), but disruption of mitonuclear interactions might
result in adverse health outcomes (Reinhardt et al., 2013) or, in the
long term, to reproductive isolation ultimately leading to allopatric speciation (Barreto and Burton, 2013). Further evidence for an effect on
fitness comes from D. melanogaster. When distinct naturally occurring
mitochondrial genomes were placed against an isogenic nuclear background, gene expression was influenced by male-specific polymorphisms
and led to male-specific modifications of nuclear gene expression
(1500 genes), indicating a pervasive retrograde signalling between
the genomes (Innocenti et al., 2011). Other studies underline the role
of mitonuclear interactions in determining key fitness traits and
adverse health effects in other species (reviewed in Reinhardt et al.,
2013). Outcomes of these epistatic interactions also depend on the environment, indicating that mitonuclear interactions evolve in response to
natural pressures on the population [reviewed in (Wolff et al., 2014)].
Mitonuclear incompatibilities increase when the genetic distance
becomes larger, e.g. when human cells lines are depleted of their
mtDNA, repopulation with mtDNA of primates cannot restore the
OXPHOS activity in these cells (Kenyon and Moraes, 1997). Although
no evidence exists for such a role of mitonuclear interactions in human
outbred populations (Chinnery et al., 2014), long-term implications
have not been well studied and only address the paternal mitonuclear
interactions (Reinhardt et al., 2013). This is obviously a concern for
NGT, as during NGT the maternal mitonuclear interaction is also disrupted, the impact of which is unknown. The only experimental evidence
of four healthy macaques born after mitochondrial replacement seems
reassuring (Tachibana et al., 2013), but the consequences until the age
of reproduction are not known and recent studies suggest that deleterious effects of mitonuclear incompatibilities will mainly manifest during
adulthood (Reinhardt et al., 2013).
Mitonuclear interactions can also be involved in the way either
mtDNA mutations or nuclear genes manifest. The reduced penetrance
of homoplasmic mutations in, for example, Leber’s Hereditary Optic
Neuropathy (LHON) and the sex differences could be explained by a
role for the nuclear genome or the environment or both, although the
full picture is not yet clear (Wolff et al., 2014). Also, mtDNA variations
can have a moderate effect on mitochondrial function, not leading to
severe mitochondrial diseases, but contributing to the severity of
other genetic or non-genetic disorders, where energy metabolism is a
critical factor. In genetic disorders, mtDNA variants or haplogroups
may rescue or deteriorate nuclear gene mutations, thereby modifying
the severity of disease expression, as has been observed in cardiomyopathies (Strauss et al., 2013). Further study is needed to elucidate the
modifying effect of mitonuclear interactions in health and disease,
which potentially adds to the complexity of mitochondrial diseases,
but could also lead to disease prevention when epistatic relations can
be matched (Moreno-Loshuertos et al., 2011). A final observation
with respect to mitonuclear interactions relates to the difference in the
distribution of heteroplasmic mutations over singe cells (oocytes, fibroblasts, blastomeres), which can be random or skewed and which could
be the result of a nuclear factor (Blok et al., 1997). Evidence exists
from mice studies, in which diverse patterns of segregation are observed
among tissues, with tissue-specific selection for different mtDNA genotypes (Jenuth et al., 1997), not caused by replication efficiency or differences in OXPHOS function (Battersby and Shoubridge, 2001).
No effective therapy for mitochondrial disorders currently exists and
new options are being explored. A dysfunctional OXPHOS system is
often associated with an increased production of ROS (Vives-Bauza
et al., 2006), for which existing rescue mechanisms fall short. In such
cases, antioxidant supplementation could be used to ameliorate disease
progress. Increased oxidative stress, however, appears to be mutationand patient-specific and fibroblasts of patients can be used to estimate
the ROS damage and the potential benefit from antioxidant therapy
(Voets et al., 2012), although, at the same time, side-effects should be carefully evaluated (Bjelakovic et al., 2012). As can be learned from plants, antioxidant systems can reduce mutation loads to a lower level than in animals.
Therefore, using a heterologous gene, encoding a supplemental oxidase
(e.g. AOX), otherwise absent from mammals, has been suggested as a
possibility to neutralize increased ROS production by defective
OXPHOS [reviewed in El-Khoury et al. (2014)].
For nuclear genes, in some cases, treatments can be offered, based
on the specific gene involved (Gerards, 2014). Novel approaches are
being developed to correct the more challenging mtDNA mutations,
but gene correction or antigenomic (e.g. TALEN technology)
approaches (reviewed in Russell and Turnbull, 2014) to target the
mtDNA particularly suffer from an evolutionary drawback. Correcting
the mtDNA requires correcting a multi-copy genome with a different
code. Targeting the mitochondria is therefore quite cumbersome. An
advantage is that it is not necessary to correct all the mtDNA copies,
but it is sufficient to switch the balance to achieve a life-long effect.
Promising results have been obtained in patient-derived cells, in which
antigenomic mitoTALENs were capable of specifically eliminating
mutant mitochondrial genomes (Bacman et al., 2013). Alternative
approaches that incorporate an mtDNA-encoded protein in the
nuclear DNA require (1) correcting of the code (Nagley et al., 1988),
(2) adding an import sequence and (3) having the protein imported in
the mitochondria. From an evolutionary perspective, this is very unlikely
to be successful, as import of these proteins has not been possible
ever in eukaryotic evolution and, with only few exceptions, the 13
protein-encoding genes in the mtDNA are conserved among all
species, possibly due to high hydrophobicity, as has been demonstrated
(Perales-Clemente et al., 2011).
MtDNA disease manifestation
and transmission
De novo mutations
High mtDNA copy number together with high mutagenesis potential due
to ROS can create heteroplasmic mutations not only in somatic cells, but
also in germ cells. During mitochondrial inheritance, the high copy
682
number of the oocyte is strongly reduced (Cree et al., 2008; Wai et al.,
2008), creating an increased risk for de novo mutations reaching
functional significance and possible disease when pathogenic at the
bottom of the bottleneck (Fig. 3).
Lethal or severe de novo mtDNA disease
Given the variation in mtDNA content in oocytes and the constant timeframe of preimplantation development when no mtDNA replication
occurs, it is likely that the mtDNA copy number at the bottom of the
bottleneck can, in individual cases, be much lower than the mean of
200, increasing the risk that de novo mutations at this point reach very
high levels, as has been observed for de novo mutations that reach homoplasmy (Degoul et al., 1997; Maassen et al., 2002; Burrage et al., 2014).
For a large part of patients with mtDNA diseases, the likely cause is a
de novo mutation, although often this is based on the absence of a
family history (Thorburn, 2004; Sallevelt et al., in preparation) and
maternal material is needed to confirm whether these mutations are
really de novo. The rate of de novo pathogenic mutations above the threshold of expression is somewhere below the minimal birth prevalence of 1
in 5000 found for mtDNA disease (Elliott et al., 2008). The de novo pathogenic mtDNA mutations that reach high heteroplasmy levels will be
subject to purifying selection (see below), and be embryonically lethal
or manifest as severe, possibly fatal, disease in the offspring. As these children generally do not reproduce and the recurrence risk for the mother is
very low, this will not lead to additional patients or familial disease.
Familial (de novo) mtDNA diseases
The evolutionary presence of transmittable pathogenic heteroplasmic
mtDNA mutation in female carriers that are not subject to purifying selection creates a major burden of severe and unpredictable mtDNA diseases in their offspring and families (Fig. 3B). Unaffected maternal
relatives can be carriers as disease manifestations only occur above the
threshold of expression and can only be identified by genetic testing. It
is likely that these mutations have emerged at some moment in time as
de novo mutations in germ cells at levels below the threshold of expression and were transmitted to the offspring with varying mutation loads.
The frequency with which those mutations would occur de novo is difficult
to assess and can only be addressed by random screening of newborns
and matched maternal samples. One study (Elliott et al., 2008) indicated
that 107 in 100 000 newborns harbour 1 of the 10 assessed, most
prevalent mtDNA point mutations in their neonatal-cord blood, and
these are not detected in the maternal blood, providing a rough, probably
(under)estimated figure. Mutations found in a screen of human oocytes
have supported this high frequency (Jacobs et al., 2007).
Escaping the mtDNA bottleneck and purifying selection causes
familial disease
As the mutations giving rise to lethal or severe disorders are transmitted
at high mutation loads, this implies that purifying selection is not able to
filter out all detrimental mutations, even though some of them have profound effects at the enzymatic and clinical level. For instance, the risk of
having a child with fatal Leigh syndrome due to enzymatic deficiency of
complex V caused by ATP6 mutations is higher when maternal mutation
loads are high (Dahl et al., 2000) and no purifying selection occurs. It is
known that some genes, such as ATP6, tolerate pathogenic mutations
more, whereas other genes have a stronger signature of purifying selection, such as the highly conserved COX1 and COX2 genes (Stewart et al.,
Otten and Smeets
2008a, b), implying a stronger evolutionary pressure, most likely at the
level of the organelle. Transmitted pathogenic mutations remain as familial disease in society due to the variable expression (Taylor and Turnbull,
2005). Furthermore, mutations in tRNA and rRNA genes are found at a
much higher frequency than those in protein-encoding genes in the
mtDNA mutator mice (Stewart et al., 2008a, b), indicating a lower purifying pressure on these genes as well. This does not imply that those
mutations are moderate at the clinical level, as many of them can lead
to severe and often fatal disease [Leigh syndrome, Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS), Myoclonic Epilepsy with Ragged Red Fibers (MERRF)]. The distribution of
tolerated functionally significant variants in genes coding for proteins is
irreversibly correlated with the degree of conservation of the amino
acid, although differences between genes exist, and variants are better
tolerated in the loop and acceptor stem positions of tRNA genes
(Voets et al., 2011).
Why pathogenic mutations with a severe effect on OXPHOS function
escape purifying selection at the level of the organelle is not clear. It could
be the result of different mtDNA genomes complementing each other,
masking the biochemical defect (Ma et al., 2014). This seems unlikely for
the mutations reaching a very high embryonic mutation load as complementation would fall short in those cases. When the frequency of the heteroplasmy is low, selection is much weaker, indicating that purifying
selection is too weak to remove low frequent pathogenic heteroplasmy
(Ye et al., 2014). The net result could be that low-frequency heteroplasmic mtDNA mutations with high pathogenic potential are present at high
frequencies, potentially affecting offspring in future generations. The 10
most prevalent mtDNA mutations have a population frequency
between 1 in 155 (Ye et al., 2014) and 1 in 200 (Elliott et al., 2008), indicating an even larger pool of all pathogenic mtDNA mutations within a
population, which can be due to de novo mutations (Elliott et al., 2008)
and/or less-efficient purifying selection (Ye et al., 2014). Dramatic
changes in heteroplasmy can occur during transmission due to the
mtDNA bottleneck (Brown et al., 2001). This can be positively corroborated by a replication advantage of the mtDNA carrying the mutation or
negatively corroborated by a replication disadvantage of a mitochondrion with reduced fitness.
The combined action of the mtDNA bottleneck, purifying selection
(either on the level of the organelle or the phenotype) complementation
and replicative differences is complex and a thorough understanding is
lacking. The combined mechanisms induce a complex mtDNA disease inheritance (Fig. 3), which is difficult to understand and predict and might be
further influenced by the nuclear background. Comparison of the severe
mutations that do and do not escape purifying selection at the level of
the organelle as well as complementation and replication studies might
shed further light on the underlying mechanisms involved, which could
open up opportunities to prevent the more damaging mutations.
Fertility and viability
The mtDNA copy number is important for successful fertilization and
embryogenesis and the oocyte mtDNA content should be sufficient
for normal vertebrate development until implantation (Ebert et al.,
1988). The dependence of normal fertilization and reproduction on
mitochondria is reflected by the large mtDNA content of fertilized
oocytes compared with unfertilized oocytes (Santos et al., 2006) and is
allowed due to clonal expansion of mtDNA during oogenesis.
Evolutionary role of mtDNA in fertility and disease
683
Figure 3 Mitochondrial evolutionary mechanisms: implications for fertility, mtDNA disease risk and reproductive options. mtDNA is important for
healthy human reproduction (A) and altered mitochondrial parameters can cause fertility problems and mtDNA diseases (B and C). The mitochondrial
evolutionary systems determine the reproductive options patients have. (A) Owing to the bottleneck, a sufficient amount of mtDNA is necessary for healthy
reproduction. Whenever mtDNA mutations (red circles) are present, these are filtered out by the purifying bottleneck during oogenesis, rendering only
oocytes without mtDNA mutations (black circles). Even if de novo mutations occur during the bottleneck (red thunderbolt symbol), these mutations would
be compensated by the high numbers of mtDNA molecules without mutations (all below disease threshold). (B) In case of a low mtDNA copy number, the
risk is higher for de novo mutations to reach values above the disease threshold and affect the offspring. Usually, other oocytes are unaffected and recurrence
risk is low. PND can be offered for reassurance. If the mtDNA amount in oocytes is too low, oocytes would be unable to implant (blue oocytes) or even to
develop (red oocytes), according to the amount of mtDNA present. (C and D) Female carriers of (familial) mtDNA mutations generally produce oocytes
with different mutation loads, leading either to healthy offspring (green oocytes) with a mutation load below level of expression or to affected offspring (grey
oocytes). During PGD, the unaffected embryos can be selected. In some cases, all oocytes carry high mutation loads (D). In these patients, NGT can be a
future option, in which the nucleus of the carrier oocytes is transferred to an enucleated acceptor oocyte with healthy mtDNA molecules.
Apparently oocytes with an insufficient mtDNA amount are prevented
from being fertilized, as indicated by the low mtDNA count in degenerate
oocytes (Santos et al., 2006). In mice, it was shown that oocytes with only
4000 mtDNA copies can still be fertilized, but fail to develop after implantation and that at least 50 000 copies of mtDNA are needed in a
mature oocyte to be able to resume development after implantation,
684
which would lead to values of 1–2 and 22 at the bottom of the bottleneck (Fig. 3; Wai et al., 2010). Whether the required mtDNA levels are
the same in humans is unclear, though a clear correlation has been
observed between mtDNA content and fertilizability of oocytes.
Oocytes with fertilization failure had 152 000 mtDNA molecules
(Reynier et al., 2001), while in ovarian insufficiency, the count of
mtDNA is 100 000 (May-Panloup et al., 2005a, b). A negative correlation between fertilizability and mtDNA count explains the reduced fertility of oocytes from older women, since increasing maternal age
reduces the mtDNA levels in oocytes (de Boer et al., 1999), as well as
the developmental competence (Yamamoto et al., 2010). This is corroborated by the observation that premature ovarian failure can be caused
by dominant mutations in the replication domain of the POLG gene,
causing mtDNA depletion (Pagnamenta et al., 2006). In contrast, the
high de novo mutation rate in humans suggests that a low mtDNA copy
number at the bottom of the bottleneck could still be viable and able
to develop after implantation. This might reflect the difference between
rodent eccentric and human interstitial implantation (Wimsatt, 1975),
since a fast shift to the uterus for energy supply could indicate that
oocytes with lower mtDNA count in humans are still able to implant
and develop, but at the cost of a higher mutation risk. However, this
hypothesis is speculative and lacks proper evidence and should be
further studied to elucidate the de novo mutation risk.
An advantage of the reduced fertility associated with a low mtDNA
copy number in oocytes is that this prevents fertilization of those
oocytes which have the highest risk of de novo mtDNA mutations
(Santos et al., 2006). Nevertheless, a critical group of oocytes remains
that still can be fertilized and will lead to viable offspring, but will have,
as shown by the high de novo disease frequency, an increased risk for
de novo mtDNA mutations that can reach high levels of heteroplasmy.
If this indeed relates to the mtDNA copy number, then this would
enable the identification of those women at risk of having severely
affected children with de novo mtDNA disease. The frequency of mitochondrial disease does not justify a population-wide prenatal screening,
but this might be different if a group of women with a high a priori risk
could be identified. This should be elucidated by further studies on the
relation between mtDNA copy number and de novo disease risk.
The role of mtDNA copy number in fertility would justify supplementation of mitochondria in oocytes by injection of cytoplasm or mitochondria from donor oocytes (ooplasm) to enhance fertilization outcomes. In
bovines, ooplasm transfer was able to rescue developmentally compromised oocytes (by ethidium bromide exposure) and led to proper development (Chiaratti et al., 2011). The first results in humans have been
promising and suggest that fertilization outcomes could indeed be
improved and as successful implantations were achieved (Barritt et al.,
2001), but concerns have arisen about the health consequences in the
long term. Additionally, although the causality with observed chromosomal abnormalities has not been proved (Barritt et al., 2001), it has
led to a stop to human ooplasm transfer. Furthermore, ooplasm transfer
results in sustained, possibly detrimental, mtDNA heteroplasmy from
both donor and recipient (Brenner et al., 2000). Although most
current experimental animal models do not justify such concerns (Chiaratti et al., 2011), one should be careful, especially in terms of possible
mitonuclear disruptions, as described above, requiring studies on the
(long-term) effects of ooplasm donation (St John, 2002).
Although male fertility is still ensured even when mtDNA copy
numbers are low, mitochondrial function does determine spermatazoan
Otten and Smeets
function (Ruiz-Pesini et al., 2000). Energy for movement is thought to be
mainly regulated by the mitochondrial sheath of spermatozoa (Rawe
et al., 2007) and mitochondrial mutations can reduce sperm motility
(Holyoake et al., 2001). Although a low mtDNA content leads to
low-quality sperm (Amaral et al., 2013), sperm with abnormal semen
parameters tends to have increased mtDNA contents with lower
mtDNA integrity, most likely to compensate for the defects (Song and
Lewis, 2008). Especially, in those cases with asthenozoospermia (low
sperm motility) caused by mitochondrial defects, intracytoplasmic
sperm injection (ICSI) can be performed. During ICSI, a sperm cell is
injected directly into the oocyte, and can overcome asthenozoospermic
cases caused, for example, by a mitochondrial problem (Rawe et al.,
2007). The concern that paternal mtDNA could be sustained, whereas
it is normally degraded (St John et al., 2000) has not been confirmed in
ICSI follow-up studies and mice studies indicate that sperm mitochondria
are also degraded after ICSI (Cummins et al., 1997; Danan et al., 1999).
Human ageing
Widespread evidence exists for a role of mtDNA mutations in mammalian ageing (reviewed in Kujoth et al., 2007), such as the premature ageing
phenotype observed in mice that accumulate mtDNA mutations due to
defects in POLG proofreading activity (Trifunovic et al., 2004). This is in
line with the mitochondrial free radical theory of ageing, in which ROS
provokes accumulation of oxidative damage (e.g. mtDNA mutations)
and subsequent disruption of cellular homeostasis, which is thought to
be involved in ageing. However, a study in D. melanogaster indicated
that ROS accumulation does not directly regulate lifespan, since
increased or decreased ROS production did not change the lifespan accordingly (Sanz et al., 2010), suggesting another mitochondrial parameter must be dictating the ageing process. In line with these
observations, it was recently shown that the frequency of low-level mutations present at birth does not change significantly with age, implying no
increased mtDNA mutation rate during ageing and that pathogenic
mtDNA mutations that are already present early in life (before 20
years of age) cause the major disease burden. Indeed, as discussed
above, although female germ cells are generally well preserved against
mtDNA mutagenesis, the system is not perfect (e.g. de novo mutations,
escaping selection) and low-level mtDNA heteroplasmy is common
(Elliott et al., 2008; Payne et al., 2013; Ye et al., 2014). Clonal expansion
of these pre-existing mtDNA mutations occurs, which can lead to ageing
due to mitochondrial dysfunction (e.g. COX deficiency) (Greaves et al.,
2014). A (new) mutation can reach homoplasmy in 70 generations of
cell divisions (Ye et al., 2014), which takes 40 years for post-mitotic
tissues (Elson et al., 2001b) such as skeletal muscle and neurons.
Somatic mtDNA mutations that contribute to ageing might originate
after re-initiation of replication after embryo implantation (Shoubridge,
2000), beyond the action of selective evolutionary processes (bottleneck
and purifying selection) (Greaves et al., 2014), but can also be inherited.
This does not completely preclude a role for ROS production in the
ageing process, since correlations between ROS and lifespan exist
(Sanz et al., 2010) and the mutagenesis potential of ROS can induce
point mutations during early life, as well as accelerate the accumulation
of mutations. If clonal expansion of early mtDNA mutations is underlying
ageing, mutations that originate de novo somatically later in life are no major
contributors to ageing. In agreement with the clonal-expansion hypothesis, a clear relationship between antioxidant therapy supplementation
685
Evolutionary role of mtDNA in fertility and disease
and longevity is lacking (reviewed in Fusco et al., 2007). Possibly, prevention of ROS-induced mutations early in life (,20 years of age) is more
helpful, which might be achieved by antioxidants and dietary restriction.
Dietary restriction has been shown to clearly increase lifespan when
applied in several species, including rhesus monkeys (Colman et al., 2014).
Interventions that reduce mtDNA copy number can induce a somatic
bottleneck that can accelerate clonal expansion of point mutations
leading to premature ageing or age-related mitochondrial disease, e.g.
the mitotoxicity observed during HIV treatment with anti-retroviral
drug administration in some patients (Payne et al., 2011). Most likely,
POLG and subsequently mtDNA replication can be inhibited by
nucleotide-analogue reverse-transcriptase inhibitors (NRTIs) administered for HIV treatment, leading to mtDNA depletion (Gardner et al.,
2013) and subsequent pathology due to the clonal expansion of preexisting age-related somatic mtDNA mutations (Payne et al., 2011).
Since POLG is of viral origin, this system can be vulnerable to medications
that are supposed to target viral systems (Kohler and Lewis, 2007).
Concluding remarks
The mitochondria with their own genome were indispensable for the
success of eukaryotic development and the existence of complex, multicellular organisms, such as in the end human beings. However, every
success has a price and in individual human beings, this price consists
of mitochondrial and mtDNA-related diseases orders, infertility and
(accelerated) ageing-related diseases. The consequences of mitochondrial evolution on fertility, reproduction and offspring are summarized
in Fig. 3. This review demonstrates that evolutionary studies contribute
significantly to identify and understand the underlying mechanisms,
which is of key importance for
† designing successful gene replacement or antigenomic strategies to
correct mtDNA defects;
† identifying the risk of women having children with mtDNA diseases, in
exploring the safety of innovative (reproductive) treatments, such as
NGT which potentially disrupts the common, evolutionary important
mitonuclear interactions in order to prevent transmission of mtDNA
diseases;
† options to treat mtDNA-related female infertility, which might have a
similar drawback;
† ameliorating mitochondrial disease by ROS protection; and
† preventing or altering drug- or age-induced mtDNA-related pathology.
Theodosius Dobzhansky stated that ‘Nothing in biology makes sense
except in the light of evolution’ and this seems particularly the case for
genetics and reproduction.
Acknowledgements
We thank Radek Szklarczyk and Mike Gerards for their valuable comments that improved this manuscript. Maurice van Opdorp is acknowledged for his contribution in improving the quality of the figures.
Authors’ roles
A.O. and H.S. critically reviewed the literature and wrote the paper
together.
Funding
We acknowledge GROW, School for Oncology and Developmental
Biology, Maastricht University Medical Centre, for their generous
support.
Conflict of interest
None of the authors has any conflict of interest.
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