BBA - Bioenergetics (v.1858, #8)

Mitochondria in cancer by Giuseppe Gasparre; Rodrigue Rossignol; Pierre Sonveaux (553-555).

Cancer metabolism in space and time: Beyond the Warburg effect by Pierre Danhier; Piotr Bański; Valéry L Payen; Debora Grasso; Luigi Ippolito; Pierre Sonveaux; Paolo E Porporato (556-572).
Altered metabolism in cancer cells is pivotal for tumor growth, most notably by providing energy, reducing equivalents and building blocks while several metabolites exert a signaling function promoting tumor growth and progression. A cancer tissue cannot be simply reduced to a bulk of proliferating cells. Tumors are indeed complex and dynamic structures where single cells can heterogeneously perform various biological activities with different metabolic requirements. Because tumors are composed of different types of cells with metabolic activities affected by different spatial and temporal contexts, it is important to address metabolism taking into account cellular and biological heterogeneity. In this review, we describe this heterogeneity also in metabolic fluxes, thus showing the relative contribution of different metabolic activities to tumor progression according to the cellular context. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Cancer; Metabolism; Mitochondria; Heterogeneity; Metastasis;

NO control of mitochondrial function in normal and transformed cells by Celia H. Tengan; Carlos T. Moraes (573-581).
Nitric oxide (NO) is a signaling molecule with multiple facets and involved in numerous pathological process, including cancer. Among the different pathways where NO has a functionally relevant participation, is the control of mitochondrial respiration and biogenesis. NO is able to inhibit the electron transport chain, mainly at Complex IV, regulating oxygen consumption and ATP generation, but at the same time, can also induce increase in reactive oxygen and nitrogen species. The presence of reactive species can induce oxidative damage or participate in redox signaling. In this review, we discuss how NO affects mitochondrial respiration and mitochondrial biogenesis, and how it influences the development of mitochondrial deficiency and cancer. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Nitric oxide; Nitric oxide synthase; Mitochondria; Cancer; Respiratory chain;

Mitochondrial metabolism and energy sensing in tumor progression by Luisa Iommarini; Anna Ghelli; Giuseppe Gasparre; Anna Maria Porcelli (582-590).
Energy homeostasis is pivotal for cell fate since metabolic regulation, cell proliferation and death are strongly dependent on the balance between catabolic and anabolic pathways. In particular, metabolic and energetic changes have been observed in cancer cells even before the discovery of oncogenes and tumor suppressors, but have been neglected for a long time. Instead, during the past 20 years a renaissance of the study of tumor metabolism has led to a revised and more accurate sight of the metabolic landscape of cancer cells. In this scenario, genetic, biochemical and clinical evidences place mitochondria as key actors in cancer metabolic restructuring, not only because there are energy and biosynthetic intermediates manufacturers, but also because occurrence of mutations in metabolic enzymes encoded by both nuclear and mitochondrial DNA has been associated to different types of cancer. Here we provide an overview of the possible mechanisms modulating mitochondrial energy production and homeostasis in the intriguing scenario of neoplastic cells, focusing on the double-edged role of 5′-AMP activated protein kinase in cancer metabolism. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: ATP; Energy production; Mitochondria; OXPHOS; AMPK; Cancer;

Molecular and metabolic features of oncocytomas: Seeking the blueprints of indolent cancers by Monica De Luise; Giulia Girolimetti; Bernard Okere; Anna Maria Porcelli; Ivana Kurelac; Giuseppe Gasparre (591-601).
Oncocytic tumors are a peculiar subset of human neoplasms in which mitochondria have been proven to have a prominent role. A number of paradoxes render these clinical entities interesting from the translational research point of view. Most oncocytic tumors are generally metabolically constrained due to the impaired respiratory capacity and lack of the ability to respond to hypoxia, yet they maintain features that allow them to strive and persist in an indolent form. Their unique molecular and metabolic characteristics are an object of investigation that may reveal novel ways for therapeutic strategies based on metabolic targeting. With this aim in mind, we here examine the current knowledge on oncocytomas and delve into the molecular causes and consequences that revolve around the oncocytic phenotype, to understand whether we can learn to design therapies from the dissection of benign neoplasms. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Oncocytic tumors; Mitochondrial DNA mutations; Mitochondrial biogenesis; Autophagy; Mitophagy; Respiratory complex I;

Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection by Satish Srinivasan; Manti Guha; Anna Kashina; Narayan G. Avadhani (602-614).
Mitochondrial dysfunction is a hallmark of many diseases. The retrograde signaling initiated by dysfunctional mitochondria can bring about global changes in gene expression that alters cell morphology and function. Typically, this is attributed to disruption of important mitochondrial functions, such as ATP production, integration of metabolism, calcium homeostasis and regulation of apoptosis. Recent studies showed that in addition to these factors, mitochondrial dynamics might play an important role in stress signaling. Normal mitochondria are highly dynamic organelles whose size, shape and network are controlled by cell physiology. Defective mitochondrial dynamics play important roles in human diseases. Mitochondrial DNA defects and defective mitochondrial function have been reported in many cancers. Recent studies show that increased mitochondrial fission is a pro-tumorigenic phenotype. In this paper, we have explored the current understanding of the role of mitochondrial dynamics in pathologies. We present new data on mitochondrial dynamics and dysfunction to illustrate a causal link between mitochondrial DNA defects, excessive fission, mitochondrial retrograde signaling and cancer progression. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.Display Omitted
Keywords: Mitochondrial dysfunction; retrograde signaling; mitochondrial dynamics; mitochondrial fission; cancer;

Calcium regulates cell death in cancer: Roles of the mitochondria and mitochondria-associated membranes (MAMs) by Alberto Danese; Simone Patergnani; Massimo Bonora; Mariusz R. Wieckowski; Maurizio Previati; Carlotta Giorgi; Paolo Pinton (615-627).
Until 1972, the term ‘apoptosis’ was used to differentiate the programmed cell death that naturally occurs in organismal development from the acute tissue death referred to as necrosis.Many studies on cell death and programmed cell death have been published and most are, at least to some degree, related to cancer. Some key proteins and molecular pathways implicated in cell death have been analyzed, whereas others are still being actively researched; therefore, an increasing number of cellular compartments and organelles are being implicated in cell death and cancer. Here, we discuss the mitochondria and subdomains of the endoplasmic reticulum (ER) that interact with mitochondria, the mitochondria-associated membranes (MAMs), which have been identified as critical hubs in the regulation of cell death and tumor growth. MAMs-dependent calcium (Ca2+) release from the ER allows selective Ca2+ uptake by the mitochondria. The perturbation of Ca2+ homeostasis in cancer cells is correlated with sustained cell proliferation and the inhibition of cell death through the modulation of Ca2+ signaling. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Calcium (Ca2+); Apoptosis; Autophagy; Mitochondria associated membranes (MAMs); Endoplasmic reticulum; Tumor;

Reactive oxygen species (ROS) largely originating in the mitochondria play essential roles in the metabolic and (epi)genetic reprogramming of cancer cell evolution towards more aggressive phenotypes. Recent studies have indicated that the activity of superoxide dismutase (SOD2) may promote tumor progression by serving as a source of hydrogen peroxide (H2O2). H2O2 is a form of ROS that is particularly active as a redox agent affecting cell signaling due to its ability to freely diffuse out of the mitochondria and alter redox active amino acid residues on regulatory proteins. Therefore, there is likely a dichotomy whereas SOD2 can be considered a protective antioxidant, as well as a pro-oxidant during cancer progression, with these effects depending on the accumulation and detoxification of H2O2. Glutathione peroxidase-1 GPX1, is a selenium-dependent scavenger of H2O2 which partitions between the mitochondria and the cytosol. Epidemiologic studies indicated that allelic variations in the SOD2 and GPX1 genes alter the distribution and relative concentrations of SOD2 and GPX1 in mitochondria, thereby affecting the dynamic between the production and elimination of H2O2. Experimental and epidemiological evidence supporting a conflicting role of SOD2 in tumor biology, and epidemiological evidence that SOD2 and GPX1 can interact to affect cancer risk and progression indicated that it is the net accumulation of mitochondrial H2O2 (mtH2O2) resulting from of the balance between the activities SOD2 and anti-oxidants such as GPX1 that determines whether SOD2 prevents or promotes oncogenesis. In this review, research supporting the idea that GPX1 is a gatekeeper restraining the oncogenic power of mitochondrial ROS generated by SOD2 is presented. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Oxidative stress; Cancer; Manganese superoxide dismutase; Selenium; Glutathione peroxidase;

Dysregulation of mitophagy in carcinogenesis and tumor progression by Joon Young Chang; Hyon-Seung Yi; Hyeon-Woo Kim; Minho Shong (633-640).
The mitochondrial role in carcinogenesis and cancer progression is an area of active research, with many unresolved questions. Various aspects of altered mitochondrial function have been implicated in tumorigenesis and tumor progression, including mitochondrial dysfunction, a metabolic switch to aerobic glycolysis, and dysregulation of mitophagy. Mitophagy is a highly specific quality control process which eliminates dysfunctional mitochondria and promotes mitochondrial turnover, and is involved in the adaptation to nutrient stress by controlling mitochondrial mass. The dysregulation of mitochondrial turnover has both a positive and negative role in cancer. This review will begin with a basic overview of the molecular mechanisms of mitophagy, and highlight recent trends in mitophagy from cancer studies. We will conclude this review by discussing areas of research in normal mitophagy that have yet to be explored in the context of cancer such as mitochondrial proteases, the mitochondrial unfolded protein response, and mitokine action. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Mitophagy; Cancer; Mitochondrial unfolded protein response; Mitokine;

Expression and putative role of mitochondrial transport proteins in cancer by Oleksandr Lytovchenko; Edmund R.S. Kunji (641-654).
Cancer cells undergo major changes in energy and biosynthetic metabolism. One of them is the Warburg effect, in which pyruvate is used for fermentation rather for oxidative phosphorylation. Another major one is their increased reliance on glutamine, which helps to replenish the pool of Krebs cycle metabolites used for other purposes, such as amino acid or lipid biosynthesis. Mitochondria are central to these alterations, as the biochemical pathways linking these processes run through these organelles. Two membranes, an outer and inner membrane, surround mitochondria, the latter being impermeable to most organic compounds. Therefore, a large number of transport proteins are needed to link the biochemical pathways of the cytosol and mitochondrial matrix. Since the transport steps are relatively slow, it is expected that many of these transport steps are altered when cells become cancerous. In this review, changes in expression and regulation of these transport proteins are discussed as well as the role of the transported substrates. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Mitochondrial metabolism; Regulation in cancer; Transporters; Mitochondrial carrier; Pyruvate carrier; Cancer metabolism;

Acquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochondria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the development of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the ‘contract of endosymbiosis’ represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This important property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Cancer cell; Metabolic flexibility; Mitochondrial respiration; Uncoupling; Hypoxia-inducible factor; Chemoresistance;

VDAC in cancer by N.M. Mazure (665-673).
The voltage-dependent anion channel (VDAC) is a pore located at the outer membrane of the mitochondrion. It allows the entry and exit of numerous ions and metabolites between the cytosol and the mitochondrion. Flux through the pore occurs in an active way: first, it depends on the open or closed state and second, on the negative or positive charges of the different ion species passing through the pore. The flux of essential metabolites, such as ATP, determines the functioning of the mitochondria to a noxious stimulus. Moreover, VDAC acts as a platform for many proteins and in so doing supports glycolysis and prevents apoptosis by interacting with hexokinase, or members of the Bcl-2 family, respectively. VDAC is thus involved in the choice the cells make to survive or die, which is particularly relevant to cancer cells. For these reasons, VDAC has become a potential therapeutic target to fight cancer but also other diseases in which mitochondrial metabolism is modified. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor ‘a distance’. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [13C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [13C] can also be used to evaluate tumor metabolism and to follow the efficiency of a treatment at a preclinical or clinical stage. Relevant descriptors of tumor metabolism are now required to better stratify patients for the development of personalized metabolic medicine.In this review, we discuss the current limitations in basic research and drug discovery in the field of cancer metabolism to foster the need for more clinically relevant target identification and validation. We discuss the design of adapted drug screening assays and compound efficacy evaluation methods for the discovery of innovative anti-cancer therapeutic approaches at the level of tumor energetics. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.Display Omitted
Keywords: Metabolic drug discovery; Metabolic symbiosis; Macroenvironment; Microenvironment;

Mitochondria and cancer chemoresistance by Flora Guerra; Arnaldo A. Arbini; Loredana Moro (686-699).
Mitochondria, known for more than a century as the energy powerhouse of a cell, represent key intracellular signaling hub that are emerging as important determinants of several aspects of cancer development and progression, including metabolic reprogramming, acquisition of metastatic capability, and response to chemotherapeutic drugs. The majority of cancer cells harbors somatic mutations in the mitochondrial genome (mtDNA) and/or alterations in the mtDNA content, leading to mitochondrial dysfunction. Decreased mtDNA content is also detected in tumor-initiating cells, a subpopulation of cancer cells that are believed to play an integral role in cancer recurrence following chemotherapy. Although mutations in mitochondrial genes are common in cancer cells, they do not shut down completely the mitochondrial energy metabolism and functionality. Instead, they promote rewiring of the bioenergetics and biosynthetic profile of a cancer cell through a mitochondria-to-nucleus signaling activated by “dysfunctional” mitochondria that results in changes in transcription and/or activity of cancer-related genes and signaling pathways. Different cancer cell types may undergo different bioenergetic changes, some to more glycolytic and some to more oxidative. These different metabolic signatures may coexist within the same tumor mass (intra-tumor heterogeneity). In this review we describe the current understanding of mitochondrial dysfunction in the context of cancer chemoresistance with special attention to the role of mtDNA alterations. We put emphasis on potential therapeutic strategies targeting different metabolic events specific to cancer cells, including glycolysis, glutaminolysis, oxidative phosphorylation, and the retrograde signaling, to prevent chemoresistance. We also highlight novel genome-editing strategies aimed at “correcting” mtDNA defects in cancer cells. We conclude on the importance of considering intratumor metabolic heterogeneity to develop effective metabolism-based cancer therapy that can overcome chemoresistance. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Mitochondria; Mitochondrial DNA; Cancer chemoresistance;

Tumor hypoxia has long been considered as a detrimental factor for the response to irradiation. In order to improve the sensitivity of tumors cells to radiation therapy, tumor hypoxia may theoretically be alleviated by increasing the oxygen delivery or by decreasing the oxygen consumption by tumor cells. Mathematical modelling suggested that decreasing the oxygen consumption should be more efficient than increasing oxygen delivery in order to alleviate tumor hypoxia. In this paper, we review several promising strategies targeting the mitochondrial respiration for which alleviation of tumor hypoxia and increase in sensitivity to irradiation have been demonstrated. Because the translation of these approaches into the clinical arena requires the use of pharmacodynamics biomarkers able to identify shift in oxygen consumption and tumor oxygenation, we also discuss the relative merits of imaging biomarkers (Positron Emission Tomography and Magnetic Resonance) that may be used for therapeutic guidance. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.Display Omitted
Keywords: Tumor hypoxia; Tumor metabolism; Oxygen consumption; Radiotherapy; Imaging; Biomarkers;

Energy metabolism in skin cancers: A therapeutic perspective by Mohsen Hosseini; Zeinab Kasraian; Hamid Reza Rezvani (712-722).
Skin cancers are the most common cancers worldwide. The incidence of common skin cancers, including basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) and melanomas, continues to rise by 5 to 7% per year, mainly due to ultraviolet (UV) exposure and partly because of aging. This suggests an urgent necessity to improve the level of prevention and protection for skin cancers as well as developing new prognostic and diagnostic markers of skin cancers. Moreover, despite innovative therapies especially in the fields of melanoma and carcinomas, new therapeutic options are needed to bypass resistance to targeted therapies or treatment's side effects.Since reprogramming of cellular metabolism is now considered as a hallmark of cancer, some of the recent findings on the role of energy metabolism in skin cancer initiation and progression as well as its effect on the response to targeted therapies are discussed in this review. This article is part of a Special Issue entitled Mitochondria in cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.
Keywords: Melanoma; Carcinoma; Warburg effect; Mitochondria; Targeted therapy; Cancer biomarker; BCC; SCC;

Metabolic synthetic lethality in cancer therapy by Vincent Zecchini; Christian Frezza (723-731).
Our understanding of cancer has recently seen a major paradigm shift resulting in it being viewed as a metabolic disorder, and altered cellular metabolism being recognised as a hallmark of cancer. This concept was spurred by the findings that the oncogenic mutations driving tumorigenesis induce a reprogramming of cancer cell metabolism that is required for unrestrained growth and proliferation. The recent discovery that mutations in key mitochondrial enzymes play a causal role in tumorigenesis suggested that dysregulation of metabolism could also be a driver of tumorigenesis. These mutations induce profound adaptive metabolic alterations that are a prerequisite for the survival of the mutated cells. Because these metabolic events are specific to cancer cells, they offer an opportunity to develop new therapies that specifically target tumour cells without affecting healthy tissue. Here, we will describe recent developments in metabolism-based cancer therapy, in particular focusing on the concept of metabolic synthetic lethality. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.