Mitochondrial ros in cancer: initiators, amplifiers or an achilles' heel?

KEY POINTS * Mitochondria contribute to the generation of ATP through oxidative phosphorylation, but they also participate in biosynthetic, metabolic and signalling functions in the cell.

Some of the signalling functions are mediated by reactive oxygen species (ROS) that are generated by the electron transport chain. Alterations in mitochondrial ROS generation have been

linked to a wide range of tumour cell types. * Mitochondria generate ROS when electrons residing on flavin groups, iron–sulphur centres or other electron transport 'way-stations'

are diverted to O2, generating superoxide. Diverse 'antioxidant enzymes' scavenge ROS and/or reverse the effects of ROS on proteins, lipids and DNA, thereby limiting the scope of

oxidative damage or redox signalling. * Mitochondrial ROS generation can be important in cancer because it activates cellular redox signalling that drives proliferative responses and

triggers activation of transcription factors that promote tumorigenesis and survival, such as hypoxia-inducible factors (HIFs). Hypoxia triggers a paradoxical increase in the release of ROS

from complex III to the mitochondrial intermembrane space, facilitating signalling, cell survival and proliferation. * Mitochondrial DNA can be damaged by ROS, and mutant mitochondrial

proteins can augment ROS generation, creating a vicious cycle that contributes to cancer initiation or progression. Mitochondrial DNA mutations have been linked to a wide range of cancer

types. In some cases, mitochondrial DNA mutations regulate the tumorigenic phenotype through their effect on ROS generation. * Mitochondrial ROS can contribute to genomic instability, and

can contribute to the activation of mitochondria-dependent cell death pathways. However, a fuller understanding of the how altered mitochondrial ROS generation contributes to cancer

progression is needed. * Oncogenes such as _KRAS_ and _MYC_ drive tumorigenesis in part by augmenting mitochondrial ROS generation. * As many tumour cells benefit from mitochondria-derived

redox signalling, a useful therapeutic approach could revolve around the inhibition of tumour-promoting mitochondrial ROS signalling without interfering with ATP production. Such an approach

could limit the ability of cells to activate protective responses, leaving them vulnerable to cytotoxic agents. ABSTRACT Mitochondria cooperate with their host cells by contributing to

bioenergetics, metabolism, biosynthesis, and cell death or survival functions. Reactive oxygen species (ROS) generated by mitochondria participate in stress signalling in normal cells but

also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and

accelerate the accumulation of additional mutations that lead to metastatic behaviour. As mitochondria carry out important functions in normal cells, disabling their function is not a

feasible therapy for cancer. However, ROS signalling contributes to proliferation and survival in many cancers, so the targeted disruption of mitochondria-to-cell redox communication

represents a promising avenue for future therapy. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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Scholar  Download references ACKNOWLEDGEMENTS The authors were supported by the US National Institutes of Health (NIH) Grants HL35440 and HL122062. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA Simran S. Sabharwal & Paul T. Schumacker Authors * Simran S.

Sabharwal View author publications You can also search for this author inPubMed Google Scholar * Paul T. Schumacker View author publications You can also search for this author inPubMed 

Google Scholar CORRESPONDING AUTHOR Correspondence to Paul T. Schumacker. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. POWERPOINT SLIDES

POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 GLOSSARY * Mitochondria Organelles within eukaryotic cells that participate in

energy production, biosynthetic processes, redox regulation, cell survival, signalling and cell death pathways. * ATP (Adenosine triphosphate). A high-energy molecule that is hydrolysed by

enzymes to provide the exergonic free energy required to carry out endergonic reactions. * Hypoxia A condition in which the molecular oxygen concentration is decreased relative to normal

physiological levels. * Reactive oxygen species (ROS). Reactive molecules generated by the reduction of O2 with a single electron (superoxide), two electrons (hydrogen peroxide) or three

electrons (hydroxyl radical). * ROS signalling (Reactive oxygen species signalling). A cellular signal transduction mechanism involving oxidation–reduction reactions, usually resulting in a

reversible alteration of protein structure and function that elicits a subsequent cellular response. ROS signalling frequently involves redox alterations of cysteine thiol (SH) groups in

proteins. * Free radical A molecule or atom containing an unpaired valence electron that renders it chemically reactive. Free radicals can potentially oxidize or reduce other molecules. *

Tricarboxylic acid cycle (TCA cycle). A system within mitochondria that participates in intermediary metabolism involved in energy production, inter-conversion of metabolites, and synthesis

of small molecules needed for lipid or protein synthesis. * NADPH A cofactor that is used by enzymes mediating electron transfer steps in energy production, lipid and nucleic acid synthesis,

and the maintenance of intracellular oxidation–reduction status. * Superoxide dismutases A family of enzymes that redistribute electrons between two superoxide anions to form a single

molecule of hydrogen peroxide. * Hypoxia-inducible factors (HIFs). A family of heterodimeric transcription factors that become activated during hypoxia or pseudohypoxia in a cell, and are

responsible for potentially altering the expression of hundreds of genes involved in regulating cellular responses to hypoxia. * Mitochondrial DNA (mtDNA). Circular loops of DNA containing ∼

16.6 kilobases, located in the matrix of mitochondria. This DNA encodes 13 proteins, ribosomal RNAs and transfer RNAs that are required for a functional oxidative phosphorylation system. *

Cybrids Experimental cells that are formed by fusing a cell lacking mitochondrial DNA with an enucleated cytoplast containing mutant mitochondria. * Pseudohypoxic activators Stimuli that

trigger activation of cellular responses to hypoxia, even though the O2 level in the cell is normal. * AMP-activated protein kinase (AMPK). A complex consisting of three proteins that has a

central role in the regulation of cellular energy production and energy utilization. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Sabharwal, S.,

Schumacker, P. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?. _Nat Rev Cancer_ 14, 709–721 (2014). https://doi.org/10.1038/nrc3803 Download citation *

Published: 24 October 2014 * Issue Date: November 2014 * DOI: https://doi.org/10.1038/nrc3803 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:

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