Seminars in Cancer Biology xxx (xxxx) xxx–xxx

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Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Review

Bacterial infection increases risk of carcinogenesis by targeting

mitochondria
⁎
Jesper A.B. Strickertsson, Claus Desler, Lene Juel Rasmussen
Center for Healthy Aging, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark

A R T I C L E I N F O A B S T R A C T

Keywords: As up to a fifth of all cancers worldwide, have now been linked to microbial infections, it is essential to un-
Mitochondrial function derstand the carcinogenic nature of the bacterial/host interaction. This paper reviews the bacterial targeting of
Bacterial infection mediators of mitochondrial genomic fidelity and of mitochondrial apoptotic pathways, and compares the impact
Cancer of the bacterial alteration of mitochondrial function to that of cancer. Bacterial virulence factors have been
DNA repair
demonstrated to induce mutations of mitochondrial DNA (mtDNA) and to modulate DNA repair pathways of the
Mutations
mitochondria. Furthermore, virulence factors can induce or impair the intrinsic apoptotic pathway. The effect of
Microbiome
Mitochondrial targeting bacterial targeting of mitochondria is analogous to behavior of mitochondria in a wide array of tumours, and this
strongly suggests that mitochondrial targeting of bacteria is a risk factor for carcinogenesis.

1. Introduction eukaryotic cells in quantities ranging from a single copy to several

There is an enormous interest and focus on the influence of the
microbiome on our health. Consequently, the way bacteria influence
and manipulate the cells of our body is becoming more and more un-
derstood. There are roughly 4 × 1013 bacteria in the human body and
approximately 3.9 × 1013 of these bacteria live in the human gut [1].
The majority of these bacteria are tolerated by our body as they are
commensal or function in symbiosis with their host. This tolerance is
mediated by communication between bacteria and host, involving
hormone-like chemicals that can signal to distant organs in the body
[2]. These bioactive compounds along with secreted bacterial meta-
bolites enables the gut bacteria to connect with the immune and hor-
mone system, the brain (the gut-brain axis) and host metabolism, as
well as other functions of the host [3,4]. Pathogenic bacteria mimics
part of this communication through the production of detrimental
metabolites and virulence factors to ensure reproductive niches and
propagation of pathogens [3,4]. This means host/pathogen commu-
nication can be carcinogenic, and as a direct result, up to a fifth of all
cancers worldwide have now been linked to microbial infections [5].
Cancer is one of the leading causes of death in developed countries, thus
understanding the role of bacteria relating to different steps of carci-
nogenesis, and the prevention of this, is of paramount importance. In-
vestigating infection associated oncogenesis will increase our under-
standing of the nature and cause of cancer development, required for
developing curative treatments and therapies.
Mitochondria are semiautonomous organelles present in almost all
thousand per cell. Mitochondria play an essential role in the intrinsic
apoptotic pathway [6] and participate in a broad range of innate im-
mune pathways. This is in part mediated by the mitochondrial antiviral
signaling protein (MAVS) that is located in the outer membrane of the
mitochondria, and propagate antiviral and antibacterial signaling by
triggering nuclear translocation of cytokines, interferons (IFN) and IFN-
stimulated genes [7,8]. Reactive oxygen species produced by the mi-
tochondria, have also been demonstrated to both promote and inhibit
an IFN response [9,10]. Finally, it has been reported that in eosinophils,
the small mitochondrial 16 Kb DNA genome (mtDNA) is ejected in re-
sponse to bacterial stimulation in a reactive oxygen species–dependent
manner, which in the extracellular space form structures with granule
proteins that are able to bind and kill bacteria, in a process that has
been compared to the formation of neutrophils extracellular traps
[11,12]. As will be reviewed here, the mitochondria are therefore at-
tractive targets for bacterial pathogens that aim to control host cell
function in order to ensure an optimal reproductive niche, and best
dissemination of pathogens.
In addition of its roles in apoptosis and the innate immune response,
mitochondria are responsible for the production of ATP by oxidative
phosphorylation, and synthesis of fundamental cellular components,
including amino acids, nucleotide, and lipid metabolism. Several at-
tributes of mitochondria can be correlated directly to risk of cancer. As
will be described later, this is the case for mitochondrial involvement in
the intrinsic apoptotic pathway, but also the ability of the organelle to
perform oxidative phosphorylation has been correlated to risk of cancer

⁎
Corresponding author.
E-mail address: lenera@sund.ku.dk (L.J. Rasmussen).

http://dx.doi.org/10.1016/j.semcancer.2017.07.003
Received 1 March 2017; Received in revised form 17 July 2017; Accepted 20 July 2017
1044-579X/ © 2017 Elsevier Ltd. All rights reserved.

Please cite this article as: Strickertsson, J.A.B., Seminars in Cancer Biology (2017), http://dx.doi.org/10.1016/j.semcancer.2017.07.003
J.A.B. Strickertsson et al.
[13,14]. Whereas an inhibition of the intrinsic apoptotic pathway in-
creases the chances of survival for a cancer cell, decrease of oxidative
phosphorylation has been coupled to an increased dependence on gly-
colysis, modulation of the transcription factor HIF-1α and others, and
mediation of an imbalance of cytosolic dNTP levels. This is related to an
increased production of intermediates needed for biosynthetic path-
ways, adaption to hypoxic and acidic environments and increase of
chromosomal instability [15–18]. All these factors have been demon-
strated to promote oncogenesis.
Due to the close resemblance of mitochondrial pathways that are
both targeted by microbial infection and affected in carcinogenesis, it is
essential to investigate whether risk of oncogenic transformation can be
increased by bacterial modulation of the mitochondria of the host. We
will in this review correlate the contemporary knowledge on impact of
bacterial regulation of the intrinsic apoptotic pathway, and modulation
of DNA repair and fidelity of the mitochondrial genome, with risk
factors identified for cancer.
1.1. Bacterial infection induces mtDNA mutations and interferes with DNA
damage response
Bacteria of our microbiome as well as pathogenic bacteria can in-
duce mitochondrial DNA mutations in our cells. The mitochondrial
genome encodes peptides essential for the function of the mitochondrial
electron transport chain (ETC) and thereby for the production of ATP by
oxidative phosphorylation. Mutations of mtDNA have been shown to
results in an aberrant ETC expression and to impair the activity of the
ETC and be correlated with a decreased capacity for oxidative phos-
phorylation [19]. In a study examining 89 European subjects, mi-
tochondrial DNA single nucleotide polymorphisms (SNPs) was found to
be strongly correlated to microbiota composition. The study found SNPs
in the displacement loop (D-loop) region as well as in the mitochondrial
complex I gene ND5, and in the gene coding for cytochrome b (CYTB)
encoding peptides of the ETC [20]. When focusing on pathogenic bac-
teria, a study examining 25 peptic ulcer patients infected with H. pylori
showed that the mitochondria of these patients had an increased
number of substitutions and numerous length heteroplasmic mutations
[21]. H. pylori lives in the stomachs of half the world’s population, and
is strongly associated with human gastric cancer [22]. This bacterium
can inject the virulence factors cytotoxin-associated gene A (CagA),
CagE, and vacuolating cytotoxin (VacA) through a type 4 secretion
system (T4SS) into the host epithelial cells [23]. In the host cytoplasm,
CagA stimulates signaling and interferes with host cellular growth,
adhesion, motility and invasion, whereas VacA encodes a mitochondrial
targeting signal [24–26]. We have previously shown that pathogenic H.
pylori infection increased mitochondrial D-loop mutations in 73 in-
fected individuals with chronic gastritis [27], and we have confirmed
these results in vitro in cell cultures of gastric epithelial cells demon-
strating significantly elevated transition mutation levels in the coding
regions of ETC component ND1 and cytochrome oxidase I gene (COI) as
well as the D-loop region following infection with H. pylori [27]. H.
pylori virulence factors CagA, CagE, and VacA were essential for in-
duction of D-loop mutations [27]. The gram positive pathogenic bac-
terium E. faecalis does not have these virulence factors however infec-
tion also induced transition mutations in the D-loop region of the
gastric epithelial cells [28], and transition mutations have been shown
to be the major mutational event found in mtDNA of human gastric
carcinomas [29]. Cellular respiration was investigated in a later study
and we found that the bacterial infections greatly reduced oxidative
phosphorylation which we often find to be correlated to an increased
rate of glycolysis [28,30]. Recent results show that above all exogenous
factors, the greatest source of mitochondrial DNA mutations is coupled
to mtDNA replication errors [31,32]. This puts the DNA repair ma-
chinery in an essential role of keeping an already high mutational load
to a minimum during replication. Repairing damaged DNA or muta-
tions introduced during replications is essential for preventing
2
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
oncogenic transformation of cells. Nuclear DNA damage repair is car-
ried out through six major repair pathways. Direct reversal, nucleotide
excision repair (NER), base excision repair (BER), mismatch repair
(MMR), recombinational repair (RER), and translesion synthesis (TLS)
[33]. These pathways, with the exception of TLS, follow the same
overall strategy, which is localization and elimination of the damage,
followed by restoration of the DNA helix. With the exception of NER, all
these nuclear repair activities have been identified in mitochondria,
however more simple and involving fewer proteins compared to the
well known and complex nuclear repair pathways [33]. Furthermore,
all these pathways are found, with certain variations, in both prokar-
yotes and eukaryotes suggesting that maintenance of genomic integrity
is a conserved and fundamental process for any cell. We and others
have shown that bacterial infections can affect DNA repair activities in
humans and mice [28,34–39]. The human mitochondria have a func-
tional MMR pathway with involvement of YB-1 in mismatch recogni-
tion and binding during mitochondrial MMR [40]. YB-1 has been shown
to interact with and regulate the activity of various repair proteins in-
volved in recombination repair, repair of single and double strand
breaks, and nuclear BER [40–44]. Focusing on mitochondrial MMR
protein YB-1 and BER subunit APE1, which is responsible for cleaving
abasic (AP) sites, we have presented evidence that show bacterial in-
duced elevation of mitochondrial mutations can likely be attributed to
bacterial targeting of host DNA repair [27,34]. We have previously
demonstrated that expression of APE1, but not the mitochondrial DNA
glycosylase OGG1, was significantly 2-fold down-regulated after H.
pylori infection. This modulation could to some extent be related to the
CagA, CagE, and VacA H. pylori virulence factors [27]. H. pylori infec-
tion is known to have a general regulatory effect on host DNA tran-
scription causing an induction or decrease in gene expression. This ef-
fect may be mediated by e.g. induction of aberrant promoter DNA
methylation or by affecting host transcription factors, thus not being
specific to the mitochondria, but influencing a global effect on host
gene expression [34–45] [46] [47]. By transiently knocking down APE1
and YB-1 using siRNA we have demonstrated a significant increase in
mtDNA mutations in gastric epithelial cell culture, indicating that these
subunits are important for mtDNA integrity [34]. We furthermore in-
vestigated the role of APE1 or YB-1 in protection of mtDNA integrity
during H. pylori infection. H. pylori infected cells with normal expres-
sion of APE1 and YB-1 accumulated less mutations in comparison to
infected cells with APE1 or YB-1 knocked-down. Because H. pylori in-
fection causes a down-regulation of mitochondrial function this differ-
ence in mtDNA mutations could be explained by a reduced mitochon-
drial activity and a lower mitochondrial turnover during infection.
In a different study on gastric epithelial cells, we have demonstrated
that E. faecalis significantly down-regulated expression of the essential
MMR subunits MSH2, MSH3, MSH6, and PMS1 [28], and H. pylori si-
milarly down-regulated these MMR subunits in mice and human cell
lines independently of virulence factors CagA, CagE, and VacA [27].
These findings correlate with in vivo studies on H. pylori infected pa-
tients that have shown impaired MMR expression in these patients,
while eradication of the bacterium, in another study, could rescue
MSH2 and MLH1 protein levels [36,38]. It is widely documented that a
compromised MMR machinery predisposes to cancer in hereditary
tumor syndromes such as Lynch syndrome and in somatic cancers [48].
Cells with impaired DNA repair mechanisms will accumulate mutations
introduced during replication or DNA lesions induced by exogenous and
endogenous agents. When affecting the nuclear DNA, this, greatly in-
creases the risk of oncogenic gene mutations and cancer formation.
1.1.1. Mutation of mtDNA in cancer
Many cancer cells are highly glycolytic at the expense of oxidative
phosphorylation. However, this is not a prerequisite for cancer forma-
tion, and some tumours have low to high levels of oxidative phos-
phorylation [49]. The efficiency of the mitochondria to perform oxi-
dative phosphorylation, depends on mutations in mtDNA, reductions in
J.A.B. Strickertsson et al.
mtDNA copy numbers, and/or reduced transcription and translation of
nuclear genes coding for mitochondrial proteins [50]. In a study on the
occurrence of mtDNA mutations in human cancers, somatic mtDNA
mutations were demonstrated to occur frequently (13–63%) in five
different types of tumours. The majority of these mutations were pre-
dicted to functionally impact the encoded peptide [51]. In two other
studies, more than 30 different cancer types from over 2000 human
cancers were sequenced. The two studies demonstrated a strong re-
plicative strand bias of the identified mutations, with predominantly C
to T and A to G transversions on the mitochondrial heavy strand
[31,32]. This strongly suggests, that the mtDNA mutations observed in
human tumours are correlated to failure of replication rather than the
result of exogenous mutagens. The occurrence of mtDNA mutations and
resulting decreased capacity to perform oxidative phosphorylation,
cannot be dismissed as a secondary response of carcinogenesis. The
invasive phenotype of human cells depleted of mtDNA can be reversed
by reintroducing exogenous wild-type mitochondria [52]. Furthermore,
construction of a cybrid cell line of prostate cancer cells harboring
specific mtDNA mutations has in nude mice been demonstrated to have
a growth advantage over cybrids of prostate cells with functional
mtDNA [53]. As a result, cybrid cancer cells with mtDNA mutations
have the potential of forming a tumor 7-fold larger than cybrid cancer
cells with functional mtDNA [53]. Furthermore, several anticancer
drugs are dependent on activity of the ETC to potentiate their antic-
ancer capabilities. Metformin is a complex I inhibitor utilized in the
treatment of diabetes. In diabetics, administration of the drug has an-
ticancer properties [54], and in a cell model system, this anticancer
attribute is dependent on a functional complex I of the ETC [55]. The
compound pancratistatin and derived analogues, have been shown to
selectively induce apoptosis in cancer cells [56]. However, the pro-
apoptotic effects on cancer cells were abrogated with the inhibition of
ETC complex II and III [56].
In summary, mutations of the mtDNA have been found to occur in
human tumours at a high frequency and the nature of the mutations
suggest reduced fidelity of mtDNA replication as a primary source of the
mutations. MtDNA alteration is directly involved in tumour progression
and not merely a consequence of it and dysfunction of the ETC results in
resistance to specific anti-cancer drugs. Distribution of mtDNA muta-
tions have in human cancers been demonstrated to be evenly dis-
tributed throughout the mtDNA [51], furthermore, the mtDNA is ex-
tremely compact with no introns. Therefore, a mutation of the mtDNA
will have the ability to affect the efficiency of mtDNA encoded peptides
and thereby affect the efficiency of the ETC and oxidative phosphor-
ylation. The reviewed mutagenic effect of several bacteria on the
mtDNA directly or indirectly through their inhibitory effects on the
mitochondrial DNA repair proteins, are therefore perfect analogues to
the mtDNA mutations demonstrated to increase risk of carcinogenesis.
Infection by H. pylori and other bacteria have furthermore been shown
to host intrinsic apoptotic regulation [57]. Therefore, bacterial induced
mtDNA mutations, interference of affect DNA damage responses, and
dysregulation of mitochondrial function, in combination with altered
apoptotic regulation may create a risk of malignant cell growth and
survival.
1.2. The intrinsic apoptotic pathway is targeted by bacteria
Apoptosis is a highly regulated cellular self-destruction process es-
sential for development, tissue homeostasis, and defense against in-
vading bacteria and virus. Apoptosis is characterized by membrane
blebbing, cell shrinkage, chromatin condensation, chromosomal DNA
fragmentation, global mRNA degradation and finally marking of the
cell for phagocytosis [6]. Deregulation of apoptosis is a primary target
of pathogenic bacteria in their establishment of reproductive niches
where an inhibition of apoptosis prevents premature destruction of
infected cells and allows bacterial intracellular replication. Induction of
apoptosis can also be beneficial for the invading bacteria, as it can
3
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
destroy cells of the immune system or facilitate pathogen dissemination
at a late stage of the microbial life cycle [58]. Mitochondria plays an
essential role in the intrinsic apoptotic pathway by releasing apoptotic
factors such as cytochrome c, in a process regulated by the Bcl-2 family
proteins and initiated by the permabilization of the outer mitochondrial
membrane. Bcl-2 proteins can be structurally and functionally divided
into three groups: inhibitors of apoptosis (Bcl-2, Bcl-x, Bcl-xL, Bcl-w,
Mcl-1 and A1), effectors of cytochrome c release (Bax, Bak, Bok, Puma
and Bcl-rambo), and triggers of apoptosis (BH3-only proteins) [59,60].
Upon stimuli, triggers of apoptosis are believed to activate Bax and Bak,
which in turn is responsible for the release of apoptotic factors [60].
Cytochrome c promotes the assembly of the apoptosome and sub-
sequent activation of caspase 9 which propagates the apoptotic cascade
[61].
1.2.1. Bacterial induction of apoptosis
Due to the essential role of mitochondria in the intrinsic apoptotic
pathway, the organelle is targeted by a multitude of bacteria. Bacterial
modulation of mitochondria to promote apoptosis is well covered in the
literature [57]. Select examples of apoptosis inducing bacteria include
the carcinogenic bacterium H. pylori which secrets the pore forming
virulence factor VacA, and induces apoptosis in dendritic cells by
translocation of cytosolic Bax to the mitochondria causing cytochrome c
release [62]. Enteropathogenic E. coli (EPEC) inject Mitochondria as-
sociated protein (Map) and EspF all of which cause loss of host mi-
tochondrial membrane potential and apoptotic cell death [63–66]. In-
ducing apoptosis is a strategy used by bacteria to avoid clearance by the
immune response and to facilitate dissemination of the pathogens.
1.2.2. Bacterial inhibition of apoptosis
Several bacterial effectors target the mitochondria to inhibit rather
than induce apoptosis. A prevention of apoptosis is especially important
for obligate intracellular bacteria, and different mechanisms have
evolved to inhibit pro-apoptotic signals and/or promote pro-survival
affecting the intrinsic apoptotic pathway. Bacteria of the genus
Chlamydia prevents the resulting release of apoptotic factors from the
mitochondria, by degradation of several members of the pro-apoptotic
BH3-only, subfamily of Bcl-2 [67]. The effect of Chlamydia on the fac-
tors is blocked when using inhibitors of the proteasome, and the ability
of the bacteria to degrade BH3-only subfamily members of Bcl-2 was
therefore suggested, and later demonstrated, to be attributed to the
chlamydial proteasome-like activity factor (CPAF), a serine protease
that is secreted from the bacteria into the host cell cytosol [67,68]. As a
result, Chlamydia infection has been shown to significantly inhibit Bax
and Bak activation in host cells, and in turn, inhibit the release of
apoptotic factors from the mitochondria, in response to treatment with
staurosporine, a potent inducer of apoptosis [69]. Chlamydia tracho-
matis (C. trachomatis) is furthermore associated with cancer develop-
ment as it promotes DNA damage and interferes with the host DNA
damage response [39]. The bacterium Anaplasma phagocytophilum (A.
phagocytophilum) can only replicate inside of short-lived eukaryotic
neutrophils. This bacterium has been shown to have anti-apoptotic
activity that, like Chlamydia, targets the effectors of cytochrome c re-
lease. The bacterium secretes the T4SS dependent virulence factor
Anaplasma translocation substrate 1 (Ats1) which is imported, in a
receptor-dependent manner, into the mitochondrial matrix of the host
cell from where it inhibits Bax activation and cytochrome c release
ensuring its own replicatory niche [70]. Where Chlamydia and A. pha-
gocytophilum inhibits Bax and Bak activation, Brucella suis and Coxiella
burnetii (C. burnetii) are examples of bacteria that instead promote the
expression of pro-survival proteins. The two bacteria have been de-
monstrated to inhibit apoptosis by inducing overexpression of the A1
gene and others of the Bcl-2 inhibitor of apoptosis subfamily [71,72].
The mechanism and factors behind this, are believed to be caused by
secretory agents from the bacteria, but the specific factors are still
unknown. Toxigenic Pasteurella multocida (P. multocida) is an example
J.A.B. Strickertsson et al.
Table 1
Bacteria that target human apoptotic pathway.
Bacteria Inhibition or induction of
apoptosis
Helicobacter pylori Induction
Enteropathogenic Escherichia coli (EPEC). Induction
Chlamydia Inhibit
Anaplasma phaogcytophilum Inhibit
Brucella suis Inhibit
Coxiella burnetii Inhibit
Pasteurella multocida Inhibit
Neisseria Inhibit
of a bacterium that induces both the activation of pro-survival factors
and inhibits effectors of cytochrome c release [73]. The bacterium
produces a 146 kDa protein toxin (PMT) that effect several transduction
pathways. PMT inhibits staurosporine induced-apoptosis, through
PI3K-dependent phosphorylation of Akt and results in the constitutive
expression of a proto-oncogene involved in proliferation, differentia-
tion, cell survival, apoptosis and tumorigenesis [73]. This allows the
activation of proteins mediating pro-survival, such as Mcl-1, Bcl-xL and
Bcl-2, as well as the inhibition of apoptotic signals by Bax or Puma [73].
Bacteria of the genus Neisseria also inhibits the release of apoptotic
factors from the mitochondria, where a bacterial factor associate di-
rectly with the mitochondrial membrane in a fashion, that is not be-
lieved to be associated with regulators of the apoptotic pathway. The
Neisseria protein porin PorB translocate into mitochondria of the host
cell, and maintains mitochondrial membrane integrity in response to
treatment with staurosporine [74]. Previously, the same group had
found similar translocation and anti-apoptotic effects after treatment
with purified PorB [75], highlighting the role of the protein as a
mediator of Neisseria’s anti-apoptotic properties. The mechanism be-
hind PorB’s effect on the mitochondrial membrane is unknown. The
protein induces neither expression or translocation of the pro-apoptotic
factors Bax and Bak and only induces early and transient expression of
Bcl-2 [76]. However, PorB co-immunoprecipitates with the mitochon-
drial protein voltage-dependent anionic channel (VDAC), and the anti-
apoptotic properties of PorB has been suggested to be associated with
this interaction [75]. Table 1 lists bacteria that target the apoptotic
pathway and their effector proteins.
1.2.3. Deregulation of mitochondrial apoptotic pathways in cancer
Deregulation of apoptosis is strongly associated with risk of cancer,
but also ischemia, neurodegenerative diseases and other [61]. In human
cancers, many components of the mitochondrial apoptosis pathway are
deregulated, resulting in a survival advantage for the cancer cell and
chemotherapeutic resistance. This modulation has been reported to
include all of the identified regulators of apoptosis [57]. In many ways,
the strategy of bacteria to inhibit apoptosis overlaps with that of cancer,
and infection with C. trachomatis, C. burnetii and P. multocida has been
associated with varying degrees of increased risk of cancer
[39,73,77,78]. It has not been conclusively demonstrated, that this
increased risk of cancer is caused by the anti-apoptotic effect of the
bacteria, but to underline the compatibility of the strategies, it has been
demonstrated that virus that inhibit apoptosis, directly relate to in-
creased tumorigenesis of infected cells [79]. Induction of apoptosis can
also be correlated to carcinogenesis. Cells surrounding an area of in-
creased cell death will increase cell turnover in order to compensate for
the loss of cells. This could drive oncogenic transformation, as new cells
have an increased risk of carrying mutations due to bacterial induced
impairment of host DNA repair mechanisms.
Seminars in Cancer Biology xxx (xxxx) xxx–xxx
Pathway modulated Effector Reference
Activate Bax vacA [62]
Mitochondrial membrane depolarisation Map and espF [63,66]
Degrades BH3 only proteins: Bim/Bod, Puma, and Bad CPAF [67,68]
Inhibits Bax Ats1 [70]
Induce expression of A1 ? [72]
Induced expression of A1/Bfl-1 and c-IAP2 ? [71]
Induce expression of Mcl-1, Bcl-xL and Bcl-2. Downregulates Bax or PMT [73]
Puma
VDAC? PorB [75]
2. Conclusions
As up to a fifth of all cancers have been linked to microbial infec-
tions [5] it is of extreme importance to fully understand the mutagenic
nature of this interaction. In this work, we have reviewed mitochondrial
properties that are both targeted by microbial infection and affected in
carcinogenesis. This include the induction of mtDNA mutations by
bacterial virulence factors and modulation of mitochondrial DNA repair
pathways. Also, the intrinsic apoptotic pathway has been demonstrated
to be both induced or impaired, by different virulence factors. Due to
their role in the intrinsic apoptotic pathway and with relaying innate
immune responses, mitochondria are targeted by a multitude of bac-
teria seeking to ensure optimal conditions for growth and propagation.
In modulating the intrinsic apoptotic pathway, bacteria affect the ex-
pression and activation of proteins that all have been identified to be
involved in various types of cancer. In respect to the effect of bacteria
on the fidelity of mtDNA, the resulting mutations are analogous to the
mutations seen with a high frequency in different tumours. Together,
this strongly suggests that mitochondrial targeting of bacteria mod-
ulates risk of carcinogenesis, and we believe that this is an important
topic in need of further investigations. Of special interest for future
investigations is the effect of more than one of these mitochondrial
properties being targeted simultaneously as the result of a co-occur-
rence of several bacteria targeting the mitochondria. Here the compo-
sition of the microbiome, rather than one specific strain, would be re-
sponsible for the modulation of the cancer risk of the host.
In addition to altering cancer risk, bacteria targeting the mi-
tochondria also have the potential to affect resistance of host cells to
specific chemotherapeutics. In itself, this deserves attention, as this
suggest a situation where a specific composition of the microbiome can
modulate the efficiency of chemotherapy, or where an induced and
controlled infection with bacteria expressing effector proteins, can in-
crease the sensitivity of cancer cells. We strongly believe that bacterial
impact on mitochondrial function should be investigated, when ex-
amining the carcinogenic effects of commensal or pathogenic bacteria
on human host cells.
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