TIMI-766; No.
of Pages 7
Opinion
Time to recognise that mitochondria
are bacteria?
Mark J. Pallen
Centre for Systems Biology, School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK
The scientific community is comfortable with recognis-
ing mitochondria as organelles that happen to be des-
cendants of bacteria. Here, I playfully explore the
arguments for and against a phylogenetic fundamental-
ism that states that mitochondria are bacteria and
should be given their own taxonomic family, the Mito-
chondriaceae. I also explore the consequences of recog-
nizing mitochondria as bacteria for our understanding of
the systemic response to trauma and for the prospects of
creating transgenic mitochondria.
The bacterial roots of the mitochondrion
The mitochondrion lies at the heart of eukaryotic cell
biology, with key roles in energy production, apoptosis,
free radical biology and intermediary metabolism [1]. Fully
integrated into the life of the cell, it functions as a subcel-
lular organelle – but its origins lie elsewhere. As long ago as
1890, German cell biologist Richard Altmann proposed
that mitochondria (or ‘Bioplasten’, as he called them) were
autonomous elemental life forms, similar to bacteria [1]. In
the first half of the 20th century, a number of investigators
made similar links between mitochondria and bacteria.
However, it was only with the discovery of mitochondrial
DNA (mtDNA) in the 1960s that the idea that mitochon-
dria were derived from bacteria gained wider acceptance,
particularly in the context of the serial endosymbiotic
theory that proposed that the eukaryotic cell originated
from multiple prokaryotic precursors [2–4]. Although some
components of this theory have been abandoned (e.g. spir-
ochaetes as precursors of eukaryotic cilia and flagella),
evidence for and acceptance of the endosymbiotic origins
of mitochondria have accumulated steadily over the past
half century and numerous extensive and deep similarities
are now recognised between mitochondria and their bac-
terial relatives (Table 1).
Most microbiologists and cell biologists are probably
already aware of the fact that mitochondria are now con-
sidered descendents of endosymbiotic bacteria and they
are comfortable with this description of the facts. However,
the way we describe the world influences the way we think
about it, so what if we abandon caution and state simply
that ‘mitochondria are bacteria’ and see where this refor-
mulation leads us? Such playful thought experiments have
a distinguished history in science, from Maxwell’s demon
to Schrödinger’s cat [5]. Bearing this in mind, I will exam-
ine the arguments for and against classifying mitochondria
as bacteria and undertake a mischievous exploration of
Corresponding author: Pallen, M.J. (m.pallen@bham.ac.uk).
0966-842X/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2010.11.001 Trends in Microbiology xx (2010) 1–7
how such a re-evaluation might change the way we think
about mitochondria, bacteria and the human condition.
Why should we classify mitochondria as bacteria?
Even if we accept the endosymbiotic origins of mitochon-
dria, why should we go one step further and classify
mitochondria as bacteria rather than simply as organelles
with bacterial ancestry? Darwin himself wrote ‘Our clas-
sifications will come to be, as far as they can be so made,
genealogies’ in the closing chapter of The Origin of Species
[6]. Darwin’s predictions came true in the latter half of the
20th century, as the system of phylogenetic or cladistic
classification (see Glossary), devised by German entomol-
ogist Willi Hennig, swept through the study of extant and
extinct organisms [7]. Central to the cladistic viewpoint
was the insistence that classification should represent only
the pattern of phylogenetic branching within a group of
Glossary
Carsonella ruddi: a gammaproteobacterial obligate endosymbiont of psyllids
(jumping plant lice) with an extremely small genome (160 kbp).
Endosymbiosis: a mutually beneficial relationship in which one organism lives
inside the other, the two effectively becoming a single biological entity.
Hodgkinia cicadicola: an alphaproteobacterial endosymbiont of the cicada
Diceroprocta semicincta with the smallest known cellular genome (144 kbp).
Hydrogenosome: a membrane enclosed organelle found in some anaerobic
ciliates, trichomonads and fungi, which generates ATP under anaerobic
conditions. Although sharing ancestry with mitochondria, most hydrogeno-
somes lack an intraorganellar genome.
Mitosome: a membrane-enclosed organelle related to mitochondria, first
described in Entamoeba histolytica, now known to occur in several other
groups of unicellular eukaryotes, including Giardia and Microsporidia.
Although sharing ancestry with mitochondria, mitosomes lack an intraorga-
nellar genome.
Monophyletic group: according to cladistic classification, a taxonomic group
that contains all and only the descendents of a single common ancestor.
Oxyrrhis marina: a marine dinoflagellate representing the earliest known
branch of the dinoflagellate lineage.
Paraphyletic group: according to cladistic classification, a taxonomic group
that contain some, but not all, descendents of a common ancestor (e.g.
reptiles).
Phylogenetic or cladistic classification: a system of biological classification
devised by Willi Hennig, which recognises only the pattern of phylogenetic
branching within lineages as taxonomically informative, insists that all taxa
should be monophyletic and ignores patterns of evolutionary innovation or
simplification.
Plastid: a class of membrane-enclosed organelle that includes chloroplasts
found in the cells of plants and algae, descended from free-living photosyn-
thetic cyanobacteria and equipped with its own intraorganellar genome.
Reclinomonas americana: a species of sessile free-living freshwater flagellate
protozoon that feeds on bacteria; each R. americana cell normally reclines
within a wineglass-shaped receptacle, the lorica, with a stem attached to an
underlying surface. The genome of the mitochondrion from R. americana
contains more functional genes than any other known mitochondrial genome.
Rickettsiales: an order of Alphaproteobacteria, all of which are obligate
intracellular endosymbionts or parasites of eukaryotic cells; according to
cladistic classification includes mitochondria.
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Opinion Trends in Microbiology xxx xxxx, Vol. xxx, No. x

Table 1. Mitochondria and bacteria: similarities and differences

Feature Similarities
Outer membrane surrounding b-Barrel porins; BamA/Omp85 outer
periplasm or intermembrane space membrane protein (OMP) assembly
machinery.
Inner membrane Rich in the distinctive lipid, cardiolipin.
Numerous small molecule transport systems.
YidC-Oxa1 membrane insertase.
Tat and Sec translocases.a
Chemiosmosis: electron transport chain pumps protons
across the inner membrane; resultant proton motive
force drives ATP synthesis via the F1 ATP synthase.
Bacterial cytoplasm/mitochondrial Contains DNA, tRNA, ribosomes and numerous
matrix soluble enzymes, including homologous Fe-S
cluster assembly machinery.
Genetics, transcription, translation Reproduction by binary fission.
Closed circular, double stranded chromosome
with unmethylated CpG islands.
Group II introns.a
Linear or circular plasmids.a
Coupled transcription/translation.
Bacterial-type rRNAs, tRNAs, mRNAs and ribosomes.
N-formylmethionine start residue in proteins.
a
These features are found in some, but not all, mitochondria.
Differences
Mitochondria lack peptidoglycan,
lipopolysaccharide, capsules,
flagella, fimbriae.
Translocase of the outer membrane
(TOM) protein complex translocates
proteins into the mitochondrial
intermembrane space, including OMPs.
Mitochondrial inner membrane highly
convoluted, with multiple invaginations
(cristae).
Mitochondria possess an ADP/ATP
translocator, exchanging organellar
ATP with cytosolic ADP.
Translocase of the inner membrane
(TIM) protein complexes translocate
proteins into inner membrane and
mitochondrial matrix.
Glycolysis originated outside
Alphaproteobacteria.
Mitochondria also capable of fusion.
Chromosomal copy number and coding
density typically higher in mitochondria.
Relaxed codon usage and variations from
the ‘universal’ code in mitochondria.a
Mitochondrial rRNA genes not amplified
by universal primers.
Key components of mitochondrial DNA
replication and transcription derived
from bacteriophage.
Most mitochondrial proteins encoded in
the nuclear genome and are imported
into the organelle.

lineages, rather than concern itself with patterns of evolu-
tionary innovation or simplification. In this view, taxonom-
ic groups should be viewed as valid only if monophyletic;
that is, containing all and only the descendents of a single
common ancestor. By contrast, paraphyletic groups that
contain some, but not all, descendents from a common
ancestor are no longer accepted as valid.
Acceptance of cladistic classification has led to several
radical rethinks in the taxonomy of animals. For profes-
sional taxonomists, birds are now recognised as dinosaurs,
whereas fish (class Pisces according to traditional taxono-
my) and reptiles (class Reptilia according to traditional
taxonomy) are no longer accepted as valid taxa, because
there is no way to define fish on grounds of common descent
without including tetrapods, or to define reptiles on
grounds of common descent without including birds. Such
changes have created a tension between popular language
and professional taxonomy; for the taxonomist, when the
person on the street says ‘dinosaur’, they really mean ‘non-
avian dinosaur’! There is also an uneasy relationship
between conventional Linnaean taxonomy, with a strict
‘one size fits all’ hierarchy of taxa (phylum, class, order,
family, genus, species) and the more flexible succession of
clades defined by phylogenetic taxonomy. In some cases,
Linnaean and cladistic taxa remain interchangeable (e.g.
Aves), but some clades do not fit well into a Linnaean
scheme at all (e.g. Amniota). The most extreme exponents
of phylogenetic classification have called for the abandon-
ment of Linnaean taxonomy altogether and its replace-
ment by a strictly phylogenetic PhyloCode [8].
Since the widespread adoption of sequence-based
approaches to the taxonomy and evolution of microorgan-
isms, phylogenetic classification has permeated microbiol-
ogy. Thus, there have been calls to abandon the term
‘prokaryote’ because this represents a paraphyletic group
(the two domains Archaea and Eukarya are believed to
share a more recent common ancestor than Archaea and
Bacteria) [9]. Similarly, mycoplasmas, once viewed as
primitive ancestor-like bacteria, are now firmly classified
along with the low G+C Gram-positive bacteria in the
phylum Firmicutes, despite the fact that mycoplasmas
lack a cell wall [10].
A wide range of molecular phylogenetic studies has been
applied to macromolecules encoded within mitochondrial
genomes and all support a bacterial or, more specifically,
an alphaproteobacterial affiliation for mitochondria [11–
17]. Thus, by the logic of cladistic classification, we have no
choice but to accept that mitochondria belong in the do-
main Bacteria, or to put it plainly, that mitochondria are
bacteria. Similar arguments apply to chloroplasts and
other plastids [18], so what we used to call bacteria should
now more accurately be termed non-organellar bacteria!
There is also a growing consensus from molecular stud-
ies that all mitochondria, irrespective of wide differences in
genome size and content, belong in one monophyletic
group. This group includes structurally similar, function-
ally distinctive organelles such as the mitosomes and
hydrogenosomes, but excludes plastids [19]. By the logic
of phylogenetic classification, the mitochondrial clade
should be given its own taxonomic name, but in Linnaean

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Opinion
taxonomy, what it should be called depends on its rank.
Molecular phylogenetic studies place mitochondria within
the class Alphaproteobacteria, but opinions differ as to
whether they represent a sister group to the order Rick-
ettsiales [13,16] or to the family Rickettsiaceae [11,17] (or
in a couple of dissident studies, belong elsewhere in the
class [15,20]). If placed alongside the Rickettsiales, the
mitochondria belong in their own order, Mitochondriales,
but wherever they are placed, they appear to merit their
own family, the Mitochondriaceae.
Even if we accept that mitochondria represent a mono-
phyletic group, originating from a single common ancestor,
we have to ask: how many genera or species should there be
within the Mitochondriaceae? Deciding how mitochondrial
lineages should be cleaved into species could turn into an
‘angels on pinhead’ argument. However, as a benchmark in
our thought experiment, a brief BLAST search shows that
the small subunit RNA gene from the human mitochondri-
al Cambridge reference sequence (NCBI Reference Se-
quence: NC_012920.1) shows 98% identity to the
equivalent gene from the Neanderthal mitochondrion
(i.e. that the two mitochondria would probably be classified
as the same species if considered as bacteria) and 92%
identity to that from the chimpanzee mitochondrion (and
thus would probably be considered different bacterial spe-
cies). It thus seems safe to conclude that all human mito-
chondria should, on this view, be classified as a single
species, which I suggest, in the spirit of creative mischief,
should be named Candidatus Mitochondrion lacksi (after
Henrietta Lacks, the most abundant source of human
mitochondria on the planet, see below), although how
many of the millions of other mitochondrial lineages of
the biosphere warrant species status remains an open
question.
Objections and counter arguments
By this stage, some of you will be spluttering with indig-
nation at the absurdity of my argument – of course mito-
chondria aren’t bacteria; they are organelles! They have
evolved into something so distinctive and so fundamentally
different that it makes no sense to continue to classify them
as bacteria. This objection can be countered by an argu-
ment from antiquity as to how much something has to
change before becoming something different. In the first
century CE, Plutarch describes the ship of Theseus, in
which each plank is replaced as it decays until none of the
original planks remain [21]. At the end of the process, is it
the same ship or not? If not, when did it change from one
ship to another? In like manner, the mitochondrial lineage
underwent multiple changes during the transition from
free-living bacterium to organelle, but are any of these
changes sufficiently distinctive or profound to overturn
arguments from phylogeny?
One obvious change is that mitochondria have under-
gone considerable genomic downsizing, in terms of genome
size and gene number. However, this process is common
to many endosymbiotic lineages inhabiting protected,
nutrient-rich intracellular environments [22,23]. In terms
of genome size, there is overlap between the largest mito-
chondrial genomes (>1 Mb in the cucumber [24]) and
even average sized bacterial genomes. In terms of gene
Trends in Microbiology xxx xxxx, Vol. xxx, No. x
numbers, mitochondria occupy one end of a spectrum, but
the gap is closing steadily between the most gene-rich
mitochondrial genome (the 69 kb, 97 gene Reclinomonas
americana mitochondrial genome) and the most gene-
depleted endosymbiont genome (the 144 kb, 188 gene
Hodgkinia cicadicola genome) [25,26].
Many mitochondrial genes have migrated to the nuclear
genome so it could be argued that they have outsourced
most of their genome. The process of integration of mito-
chondrial genomes into nuclear genomes is still ongoing; a
mutated mitochondrial genome integrated into the human
nuclear genome accounted for an erroneous report of am-
plification of (non-avian) dinosaur DNA [27]. However, it is
probable that genes from other endosymbionts migrate
into the host genome [26]. In the case of the endosymbiont
Carsonella ruddi, with its tiny 160 kb genome, it has been
suggested that the bacterium could not remain viable
without the contribution of genes from the host genome
[28,29].
An alternative tipping point in the transition from
endosymbiont to organelle occurred when the mitochon-
drion started importing proteins encoded in the host ge-
nome [30–32], but as there are several protein sorting
pathways, this is likely to have been a gradual process
[32]. It is worth noting in passing that the evolution of the
mitochondrial protein import system is not without con-
troversy, with two conflicting viewpoints: one claiming that
the outer membrane components originated from the pro-
tomitochondrion and the other claiming that they originat-
ed from the nuclear genome [33,34]. However, recent
studies have chipped away at the apparent irreducible
complexity of the import apparatus, which has been cob-
bled together gradually from various bacterial proteins
[35]. Most recently, Emelyanov showed that rickettsias
incorporate VDAC1, a mitochondrial protein encoded in
the nuclear genome, into their outer membrane [36], but
this has not led to a reclassification of these obligate
intracellular bacteria as organelles!
Taxonomists might object to the reclassifying of mito-
chondria as bacteria on practical grounds. Shoehorning so
many disparate organellar lineages associated with so
many millions of different eukaryotic species into a single
bacterial order would demand a TARDIS-like taxonomy
(larger on the inside than on the outside) and might stretch
Linnaean taxonomy to breaking point. But ardent cladists
would argue that it is broken anyway!
The idea that each eukaryotic species has to be split into
two, one species for the nuclear genome and another for the
mitochondrion, might also be seen as alarming, but tax-
onomists have solved a similar problem with lichens (fun-
gal–cyanobacterial or fungal–algal symbioses) by naming
the whole symbiosis after the majority fungal component,
so Homo sapiens could remain a valid description of the
whole human nuclear–mitochondrial symbiosis.
The polyphyletic origin of eukaryotes from a merger of
mitochondrial and nuclear lineages calls to mind another
problem, the polyphyletic origins of the mitochondrial
proteome. Although molecular phylogenetic analyses of
proteins encoded on the mitochondrial chromosome sup-
port the classification of mitochondria in the Alphaproteo-
bacteria, less than 20% of the far more numerous nuclear
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Opinion
encoded mitochondrial proteins are alphaproteobacterial
in origin [14,37,38]. In addition, whereas most of these
proteins have been recruited from the nuclear genome, it is
clear that key components of the mitochondrial transcrip-
tion and replication apparatus are derived from bacterio-
phages [39] and that most mitochondrial aminoacyl-tRNA
synthetases originate from bacteria outside the alphapro-
teobacterial lineage [40]. The problems created by wide-
spread recruitment of foreign material are not unique to
mitochondria. Some languages borrow so extensively that
their origins might be obscured; open a dictionary and you
will find that the vast majority of English words are
derived from French or Latin roots, yet few would argue
that English should no longer be considered a Germanic
language. Similarly, on grounds of continuity of descent, it
has been argued that Yiddish should be classified as a
relexified Slavic language, despite a predominantly Ger-
manic vocabulary [41].
A final objection to the proposed reassessment is on
grounds of utility. Aside from providing fodder for arm-
chair philosophizing or a pacifier to the phylogenetic fun-
damentalist, what practical use would it bring to those who
study bacteria or mitochondria? After all, microbiologists
happily retain the genus Shigella because it highlights a
distinction useful in clinical microbiology, even though a
strict adherence to phylogenetic classification would de-
mote the whole genus to one or more pathovars of the single
species, Escherichia coli. On this point, I stand my ground
by highlighting some of the ways in which a reclassification
of mitochondria as bacteria might change the way we look
at the world and even facilitate scientific progress.
Rewriting the record books and the text books
If we accept that mitochondria are bacteria, then the
record books have to be rewritten. The first bacterial
genome sequence was completed not by American arri-
viste Craig Venter and his team in 1995 [42], but instead
by a team at the Medical Research Council Laboratories in
Cambridge, England, which included double Nobel laure-
ate Fred Sanger, who completed the human mitochondrial
genome sequence in 1981 [43]! The most successful bacte-
rial clade on the planet, in terms of abundance, is no longer
SAR11 with its 1028 cells, but the Mitochondriaceae, with
1026 representatives just in the human mitochondrial
lineage, let alone in all the millions of other eukaryotic
lineages!
The most abundant mitochondrial lineage from a single
human is that of Henrietta Lacks, the African American
woman who was the source of HeLa cells [44]. Each HeLa
cell contains hundreds of mitochondria and the global
biomass of HeLa cells is hundreds or thousands times
larger than the biomass of any individual human body,
so there are likely to be >1017 HeLa mitochondria in
existence.
How we should now award the record for the smallest
bacterial genome sequence becomes a serious philosophical
problem. At 16 kbp, the human mitochondrial genome is
less than a tenth of the size of the Hodgkinia cicadicola
genome. Plasmodium has the smallest (non-zero) mito-
chondrial genome known to date: a diminutive 6 kbp,
harbouring only three protein coding genes (cox1, cox3
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Trends in Microbiology xxx xxxx, Vol. xxx, No. x
and cob) and fragments of rRNAs [45]. The mitochondrial
genome from Oxyrrhis marina (an early-branching dino-
flagellate) has the smallest known gene complement for
any (non-zero) bacterial genome, with a handful of rRNA
fragments and only two protein coding genes [46]. Howev-
er, the reductio ad absurdum comes from mitochondrial
derivatives that have lost all of their DNA; for example, the
mitosomes of Cryptosporidium or the hydrogenomsomes of
Trichomonas [47,48. Does it make sense to say that the
smallest bacterial genome is zero base pairs, or does even
the most fervent cladist have to accept that in completely
outsourcing their genomes, these bacteria have genuinely
turned into something quite different?
The ‘mitochondria as bacteria’ view means that our
textbooks need to change, as it becomes clear that mito-
chondria share so many features with their bacterial
relatives, whether in electron transport chains, the struc-
ture of the F-type ATPase, or the numerous sequence and
structural homologies that have been steadily uncovered
(Table 1). It might even be possible to arrive at a standar-
dised nomenclature that could be applied to homologous
systems in organellar and non-organellar bacteria; per-
haps it is time to ditch ‘oligomycin sensitivity conferral
protein’ in favour of AtpH?
An innate immune response to our in-house bacteria
The human innate immune response exploits pattern rec-
ognition receptors to identify pathogen associated molecu-
lar patterns (PAMPs), many of which are common
components of bacterial cells [49]. If we accept that mito-
chondria are just unusual, house-trained bacteria, how
does our innate immune system avoid recognising these
organelles as potential invaders? One answer is that many
of the best known PAMPs, such as lipopolysaccharide,
flagellin and peptidoglycan, are absent from mitochondria,
even though they were likely to have been present in their
free-living progenitors.
However, some bacterial PAMPs persist in mitochon-
dria! Mitochondrial proteins, such as those of non-organel-
lar bacteria, are N-formylated [50]. Formyl peptides are
known to activate the innate immune system’s formyl
peptide receptors (FPRs) [51]. Similarly, mitochondrial
DNA, similar to other bacterial DNA, is rich in unmethy-
lated CpG dinucleotides, making it a potential ligand for
Toll-like receptor (TLR)9 [52].
Therefore, why does the innate immune system not
recognise mitochondria as bacteria? Over the past few
years, several lines of evidence have suggested that it does!
Mitochondrial formyl peptides, released from necrotic
cells, have been shown to induce platelet and neutrophil
chemotaxis and activate monocytes [53–56]. Most recently,
Carl Hauser and his colleagues have taken the ‘mitochon-
dria are bacteria’ argument to its logical conclusion and
provided definitive evidence that the innate immune sys-
tem does indeed recognise mitochondrial bacterial motifs,
not so much as PAMPs, but as DAMPs (damage-associated
molecular patterns) released into the circulation after
cellular injury [57,58]. Hauser’s team has shown that
mitochondrial formyl peptides and DNA activate human
neutrophils through binding to FPR1 and TLR9, respec-
tively and that the resulting neutrophil migration and
TIMI-766; No. of Pages 7
Opinion
degranulation explain the associated multiorgan damage
[57,58]. The existence of an innate immune response to our
in-house bacteria explains why the systemic response to
tissue damage often mimics the response to infection,
triggering the same sepsis syndrome, a satisfying expla-
nation that might have been obvious earlier, had we been
quicker to classify mitochondria as bacteria!
Manipulating mitochondria as bacteria
The existence of a closed circular mitochondrial chromo-
some sequestered away from the nuclear genome within an
organellar bacterium provides an obvious target for genetic
manipulation. However, our ability to manipulate mito-
chondrial genomes in vertebrates lags well behind our
ability to make transgenic organisms via manipulation
of the nuclear genome; in fact, no practical means have
yet been found to re-engineer vertebrate mitochondrial
genomes. Yet, there is a clear pressing need for such
technologies, when over 200 germline mutations in the
mitochondrial genome have been associated with a range
of clinical disorders in humans [59]. Genetic manipulation
of the mitochondrial genome might allow therapeutic re-
pair of these mutations. Furthermore, somatic mutations
in the mitochondrial genome, triggered by free radicals
generated as a result of respiration, are thought to con-
tribute to aging [60]. Targeting antioxidant enzymes such
as superoxide dismutase and catalase for import into
mitochondria can extend life span in flies and mice, respec-
tively [61,62]. What if we could raid the bacterial world to
encode within the mitochondrial genome the best possible
defences against free radicals and provide this genome
with an enhanced DNA repair apparatus? Could we eradi-
cate ageing?
The mitochondrial genome also provides a handy vehi-
cle for the compartmentalised expression of exogenous
proteins or metabolic pathways, whether for use in gene
therapy (e.g. to bypass genetic defects in nuclear encoded
mitochondrial components) or as a deliberate transhuma-
nist effort to augment and improve on nature (e.g. could
vitamin C be synthesised in the mitochondrion, then
exported to the cytoplasm?). Crucially, a transgenic mito-
chondrion might be rendered susceptible to destruction in
the presence of antibiotics or other small molecules, turn-
ing transgenic mitochondria into a controllable vehicle for
exogenous gene expression that could be eradicated if
attempts at gene therapy went awry.
Therefore, having established the potential benefits of
genetic manipulation, how does the perspective that mito-
chondria are bacteria help? Three approaches are used in
genetic manipulation of bacteria: transduction, transfor-
mation and conjugation. Transduction into mitochondria
would appear to be ruled out by the absence of bacterio-
phages that target mitochondria. The fact that some mito-
chondria import some tRNAs and rRNAs suggests that
transformation might be possible; indeed, there is some
limited evidence to suggest that transformation of mito-
chondria is achievable with nucleic acids within lipid
vesicles [63]. However, conjugation looks more promising
as an efficient way of getting DNA into mitochondria,
bearing in mind that bacterial conjugation systems have
evolved to transfer DNA through a pair of bacterial mem-
Trends in Microbiology xxx xxxx, Vol. xxx, No. x
branes homologous to the mitochondrial double mem-
brane. In this context, Yoon and Koob have exploited the
‘mitochondria as bacteria’ perspective in a series of pio-
neering studies. First, they showed that it is possible to
replicate entire mitochondrial genomes as plasmids in E.
coli by introducing plasmid origins of replication into the
mitochondrial chromosome [64]. Subsequently, they
showed that a mobilisable DNA construct containing an
origin of transfer (oriT) DNA sequence could be transferred
from E. coli into isolated mammalian mitochondria
through conjugation [65]. Furthermore, they showed that
the transferred DNA could act as a substrate for transcrip-
tion within the mitochondrial matrix. Most recently, Yoon
and Koob have shown that drug resistance genes encoding
neomycin and hygromycin phosphotransferases can func-
tion as selectable markers within the mitochondrial matrix
[66].
It is easy to envisage a future research programme that
integrates and builds on these achievements and on the
‘mitochondria as bacteria’ perspective, to produce a versa-
tile toolkit for creating transgenic, or even wholly synthet-
ic, mitochondrial chromosomes or other replicons capable
of surviving and functioning within the mitochondrial
matrix. A recent study has shown that the bacterial conju-
gation machinery is functional in the mammalian cytosol
[67], so transformation by conjugation need not be limited
to isolated mitochondria; instead, it might be possible to
deliver DNA to mitochondria within eukaryotic cells (e.g.
stem cells in the bone marrow), using strains of E. coli
capable of invading eukaryotic cells. The mind boggles at
the thought of what could be achieved if our own in-house
intracellular bacteria could be turned into cloning hosts as
versatile as E. coli!
Conclusions
Many readers might not yet be ready for the brand of
phylogenetic fundamentalism that views mitochondria
as bacteria, but I hope I have convinced you that there
is scientific utility in thinking this way, for example in
relating mitochondrial sequences and structures to func-
tion, or understanding sepsis syndrome. In more practical
terms, it is time to exploit and manipulate the Mitochon-
driaceae in the service of Man, whether in simply curing
mitochondrial disease or in the spirit of Huxley’s transhu-
manism [68], enhancing the capabilities of humans and of
the animals and plants we depend on, so that we move
beyond what has already been provided by the first two
billion years of collaboration between mitochondria and
their eukaryotic hosts.
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