Seminars in Cancer Biology 47 (2017) iv–vi

Contents lists available at ScienceDirect

Seminars in Cancer Biology

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

Special Issue: Mitochondria in Cancer T

The past decade has revealed an ever-increasing number of new roles for mitochondria in the regulation of the life and death of the cell. Although
mitochondria have long been known as the subcellular sites of oxidative phosphorylation and therefore the majority of ATP synthesis, only more
recently have they been recognized for their importance in cell signaling and metabolism, proliferation, apoptosis, and for the fact that genetic and/
or metabolic alterations in mitochondria contribute to a number of diseases, including cancer. This special themed issue, Mitochondria in Cancer,
expands upon that knowledge base by offering a series of fourteen articles that review and update the many and varied roles that mitochondria play
in tumor initiation, progression, and metastasis, and explore the potential for exploiting new mitochondrial-specific targets in the effective treatment
of cancer.
Mitochondria mediate anterograde (from the nucleus to mitochondria) and retrograde (from mitochondria to nucleus) information transfer. The
evidence is now building that the role of mitochondria extends to intercellular communication as well and that the mitochondrial genome (mtDNA)
and even whole mitochondria can be transferred to and mediate information transfer between neighboring cells. Singh, Modica-Napolitano, and
Singh have defined this promiscuous information transfer function of mitochondria and mitochondrial genome as “momiome” to include all mobile
functions of mitochondria and the mitochondrial genome. The series article, Defining the momiome: Promiscuous information transfer by mobile mi-
tochondria and the mitochondrial genome, reviews the “momiome” and explores its role in cancer development, progression, and treatment [1].
Cancer stem cells (CSCs) are a subset of tumor cells that have unlimited potential for self-renewal and the ability to undertake a multiplicity of
cell fate paths. In Mitochondrial biology in cancer stem cells, Loureiro, et al. review the mitochondrial physiology of CSCs, with a focus on mi-
tochondrial signaling pathways, mitochondrial remodeling, and metabolic adaptations that contribute to CSC survival and maintenance [2]. Given
the important role that CSCs play in tumor re-growth and relapse, it is suggested that mitochondria-targeted therapies directed towards CSCs may
represent a promising new therapeutic strategy against the most aggressive types of tumors.
The internal structure of mitochondria and its cytosolic organization is controlled by various 'mitochondria-shaping' proteins, which include the
Mitofusin proteins (Mfn 1 and 2), Optic Atrophy 1 (Opa1), and dynamin-related protein 1 (Drp1). As their name implies, these proteins influence the
shape of mitochondria. Additionally, these proteins can also control the dynamic equilibrium between fusion and fission of the mitochondrial
network, the balance of which regulates several processes such as the quality of mitochondria, cell metabolism, cell death, proliferation and cell
migration, and the function of both the innate and adaptive immune systems. Interestingly, cancer cells appear to alter mitochondrial dynamics to
resist apoptosis and adjust their bioenergetic and biosynthetic needs to support tumor initiation, transformation, and metastasis. In The mitochondrial
dynamics in cancer and immune-surveillance, Simula, Nazio, and Campello review how mitochondrial dynamics can affect various processes during
cancer development, acting either directly on tumor cells or indirectly on cells responsible for tumor aggression and defense [3].
The mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress-responsive pathway that is activated by a variety of mitochondrial
perturbations and promotes mitochondrial repair, metabolic adaptations and survival by inducing anti-apoptotic factors. In Mitochondrial dysfunction
in cancer: Potential roles of ATF5 and the mitochondrial UPR, Deng, and Hayes review recent findings that suggest functions for UPRmt regulatory
components (such as the transcription factor ATF5) and transcriptional outputs (such as mitochondrial chaperones and proteases) in cancer cell
growth and survival [4].
The Tricarboxylic acid (TCA) cycle plays a central role in cellular metabolism, providing both ATP and precursors necessary for a number of
metabolic pathways. Notably, mutations in genes encoding enzymes of the TCA cycle and alterations in their expression/activity levels have de-
monstrated a direct connection between the TCA cycle and tumor formation and progression, and dysregulation of TCA cycle flux is frequently
observed in cancer. The TCA cycle as a bridge between oncometabolism and DNA transactions in cancer, by Ciccarone et al., provides an overview of the
best characterized cancer-linked alterations in TCA cycle enzymes, both regarding genetic mutations and expression levels, and describes the
molecular mechanisms by which these alterations contribute to tumor formation and progression. The impact of TCA cycle deregulation on the
control of epigenetic events and mtDNA is also discussed [5].
Mitochondria-derived reactive oxygen species (mROS) are known to induce mtDNA damage, activate oncogenes and block tumor suppressor
function, and play a critical role in the regulation of cellular signaling. In Mitochondrial ROS control of cancer, Idelchik et al. summarize the role of
mitochondria in the ROS regulation of cancer, highlight the interplay between a variety of oncogenic signaling networks, mROS and the H2O2
emitting and consuming capacity of the mitochondria, and explore targeting mROS and anti-oxidant systems in anticancer therapy [6].
Mitochondrial ribosomes, or mitoribosomes, are the translational machinery essential for the expression of mtDNA-encoded genes. In
Mitochondrial ribosomes in cancer, Kim et al. review the current knowledge regarding the dual function of mitoribosome components in protein
synthesis and apoptosis and their association with cancer susceptibility and development. The article describes the extraribosomal role of

http://dx.doi.org/10.1016/j.semcancer.2017.10.013

1044-579X/ © 2017 Published by Elsevier Ltd.

 Seminars in Cancer Biology 47 (2017) iv–vi

mitoribosome proteins in cell death regulation, addresses the association of mitoribosome proteins with cancer and the potential use of these proteins
as tumor-specific biomarkers, and explores the feasibility of targeting mitoribosome biogenesis and function for therapeutic interventions [7].
Oncocytomas are distinct tumors, which are characterized by an abnormal accumulation of defective and likely dysfunctional mitochondria in
the cell cytoplasm, but whose etiopathogenic causes have yet to be elucidated. In Etiopathogenesis of oncocytomas, Correia et al. provide an overview
of oncocytomas and describe various alterations in mitochondrial structure and function that are prevalent in these tumors, including mtDNA
mutations, increased mitochondrial biogenesis, and impaired mitophagy [8]. Further, the contributions that mitochondrial alterations might play in
oncocytic transformation and tumor progression are discussed.
In Bacterial infection increases the risk of carcinogenesis by targeting mitochondria, Strickertsson, Desler, and Rasmussen discuss the carcinogenic
nature of the bacterial/host interaction and suggest that mitochondrial targeting of bacteria is a risk factor for carcinogenesis [9]. Bacterial virulence
factors have been demonstrated to induce mutations in mtDNA and to modulate both DNA repair and apoptotic pathways in mitochondria. The
review suggests that because many of the mitochondrial alterations induced by bacterial targeting are analogous to mitochondrial alterations found
in a wide array of tumors, mitochondrial targeting of bacteria is likely a risk factor for carcinogenesis. Further, it suggests that the specific com-
position of the microbiome can modulate the efficiency of chemotherapy and that an induced and controlled infection with bacteria expressing
effector proteins might increase the sensitivity of cancer cells to chemotherapeutic agents.
Nuclear mtDNA, or NUMTs, refers to mtDNA fragments that have been transferred into the nuclear genome. Singh, Choudhury, and Tiwari have
thus defined this specific process, and more generally the transfer of any intact mitochondria or mitochondrial components into the nucleus by a new
term, "numtogenesis." The review, Numtogenesis as a mechanism for the development of cancer, explores the origin and mechanisms of mtDNA transfer
into the nucleus, and the influence of NUMTs in tumor initiation and progression [10]. Furthermore, the article summarizes results of several
previous studies, which taken together suggest that increased numtogenesis may be a factor in determining cancer risk and prognosis.
Mitophagy is a selective mode of autophagy in which mitochondria are specifically targeted for degradation at the autophagolysosome in
response to stresses such as hypoxia, nutrient deprivation, DNA damage, inflammation and mitochondrial membrane depolarization. Mitophagy
plays a central role in maintaining the mitochondrial and cellular integrity, and defects in this process can lead to loss of tissue homeostasis and
development of disease, including cancer. In Expanding perspectives on the significance of mitophagy in cancer, Drake et al. discuss how different
mitophagy adaptors and modulators, such as Parkin, BNIP3, BNIP3L, p62/SQSTM1, and OPTN, are regulated in response to physiological stresses
and deregulated in cancers [11]. Further, the article probes emerging roles for mitophagy in cell fate determination, inflammatory responses, and
DNA damage responses that contribute to our overall understanding of the role of mitophagy in cancer.
Despite recent clinical advances in cancer prevention, diagnosis, and treatment that have helped reduce overall cancer mortality rates, a distinct
disparity in these rates exist between African Americans and other ethnic populations. In Mitochondrial determinants of cancer health disparities,
Choudhury and Singh have presented a list of genetic factors and mechanisms that relate to differences in mitochondrial function in diverse
populations [12]. It is hypothesized that variants in either mitochondrial or nuclear genome-encoded mitochondrial proteins can result in suboptimal
mitochondrial function, which may underlie cancer diversity and tumor aggressiveness related to racial disparities, and that differences in mi-
tochondrial function may alter the inter-genomic cross talk that occurs between mitochondria and the nucleus and further contributes to disparities
in cancer mortality rates. It is also suggested that restoring mitochondrial function to optimal levels could enhance sensitivity to anticancer agents,
including radiation treatment of aggressive tumors, and thereby reduce some of the existing racial disparities in cancer treatment success.
In Mitochondrial dysfunction in cancer chemoprevention by phytochemicals from dietary and medicinal plants, Sehrawata et al. discuss experimental
evidence that points to mitochondrial dysfunction as a critical event leading to the generation of ROS and eventual cancer cell death by promising
phytochemicals [13]. The review further establishes the mitochondrion as a critical target of some structurally-diverse cancer chemopreventive
phytochemicals, including isothiocyanates (from cruciferous vegetables like broccoli and watercress), withaferin A (derived from a medicinal plant
Withania somnifera used heavily in Asia), and honokiol (an oriental medicine plant component).
A number of modifications in mitochondrial function are implicated in cancer biology, including a shift of energy production mechanisms,
increased ROS production and antioxidant activity, disruption of apoptotic signaling, and increased mtDNA mutation. In Current and upcoming
mitochondrial targets for cancer therapy, Kim et al. review the essential role of mitochondria in tumorigenesis, metastasis, drug resistance, and cancer
stem cell biology. Also discussed is the role of mitochondria in emerging cancer therapeutic strategies, especially cancer immunotherapy and
CRISPR-Cas9 system gene therapy [14].
The Guest Editors for this special issue of the journal Seminars in Cancer Biology hope that this series of articles will be read with interest and
enthusiasm by basic researchers and clinicians alike, and that the articles will serve as a catalyst for more robust discussion and future research
elucidating the many and varied roles of “Mitochondria in Cancer”.

Acknowledgements

We are grateful to the Editor-in-Chief. Dr. Theresa Vincent and Editorial Board members for the invitation to serve as a Guest Editors for the
special issue “Mitochondria in Cancer." We are thankful to so many of our fellow scientists and “mitochondriacs” who accepted our call for articles to
be included in this special issue. Without their contributions of time, energy, passion, and expertise, this special issue would not be possible. Finally,
yet importantly, we offer our thanks and gratitude to Carly Middendorp, Nair Rohini, and Rinky Mathew for their assistance during every step of
article processing and issue preparation.

References

[1] B. Singh, J.S. Modica-Napolitano, K.K. Singh, Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome, Semin. Cancer Biol.
(2017) .
[2] R. Loureiro, K.A. Mesquita, S. Magalhães-Novais, P.J. Oliveira, I. Vega-Naredo, Mitochondrial biology in cancer stem cells, Semin. Cancer Biol. (2017) .
[3] L. Simula, F. Nazio, S. Campello, The mitochondrial dynamics in cancer and immune-surveillance, Semin. Cancer Biol. (2017) .
[4] P. Deng, C.M. Haynes, Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR, Semin. Cancer Biol. (2017) .
[5] F. Ciccarone, R. Vegliante, L. Di Leo, M.R. Ciriolo, The TCA cycle as a bridge between oncometabolism and DNA transactions in cancer, Semin. Cancer Biol. (2017) .
[6] M.D.P.S. Idelchik, U. Begley, T.J. Begley, J.A. Melendez, Mitochondrial ROS control of cancer, Semin. Cancer Biol. (2017).
[7] H. Kim, P. Maiti, A. Barrientos, Mitochondrial ribosomes in cancer, Semin. Cancer Biol. (2017) .
[8] M. Correia, P. Pinheiro, R. Batista, Paula Soares, M. Sobrinho-Simões, V. Máximo, Etiopathogenesis of oncocytomas, Semin. Cancer Biol. (2017).
[9] J.A.B. Strickertsson, C. Desler, L.J. Rasmussen, Bacterial infection increases risk of carcinogenesis by targeting mitochondria, Semin. Cancer Biol. (2017) .

v
 Seminars in Cancer Biology 47 (2017) iv–vi

[10] K.K. Singh, A.R. Choudhury, H.K. Tiwari, Numtogenesis as a mechanism for development of cancer, Semin. Cancer Biol. (2017) .
[11] L.E. Drake, M.Z. Springer, L.P. Poole, C.J. Kim, K.F. Macleod, Expanding perspectives on the significance of mitophagy in cancer, Semin. Cancer Biol. (2017) .
[12] A.R. Choudhury, K.K. Singh, Mitochondrial determinants of cancer health disparities, Semin. Cancer Biol. (2017) .
[13] A. Sehrawat, R. Roya, S.K. Pore, E. Hahm, S.K. Samanta, K.B. Singh, S. Kim, K. Singh, S.V. Singh, Mitochondrial dysfunction in cancer chemoprevention by phytochemicals from
dietary and medicinal plants, Semin. Cancer Biol. (2017).
[14] H.K. Kim, Y.H. Noh, B. Nilius, K.S. Ko, B.D. Rhee, N. Kim, J. Han, Current and upcoming mitochondrial targets for cancer therapy, Semin. Cancer Biol. (2017) .

Keshav K Singh, Ph.D,

Department of Genetics, School of Medicine, Center for Aging, UAB Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham,
AL, USA
Department of Pathology, Department of Environmental Health, Center for Free Radical Biology, Birmingham Veterans Affairs Medical Center, Birmingham,
AL, USA
Josephine S. Modica-Napolitano, Ph.D
Department of Biology, Merrimack College, North Andover, MA, USA

vi