BBA - Bioenergetics (v.1807, #6)

Bioenergetics of cancer by Rodrigue Rossignol (533).

Oxidative phosphorylation in cancer cells by Giancarlo Solaini; Gianluca Sgarbi; Alessandra Baracca (534-542).
Evidence suggests that mitochondrial metabolism may play a key role in controlling cancer cells life and proliferation. Recent evidence also indicates how the altered contribution of these organelles to metabolism and the resistance of cancer mitochondria against apoptosis-associated permeabilization are closely related. The hallmarks of cancer growth, increased glycolysis and lactate production in tumours, have raised attention due to recent observations suggesting a wide spectrum of oxidative phosphorylation deficit and decreased availability of ATP associated with malignancies and tumour cell expansion. More specifically, alteration in signal transduction pathways directly affects mitochondrial proteins playing critical roles in controlling the membrane potential as UCP2 and components of both MPTP and oxphos complexes, or in controlling cells life and death as the Bcl-2 proteins family. Moreover, since mitochondrial bioenergetics and dynamics, are also involved in processes of cells life and death, proper regulation of these mitochondrial functions is crucial for tumours to grow. Therefore a better understanding of the key pathophysiological differences between mitochondria in cancer cells and in their non-cancer surrounding tissue is crucial to the finding of tools interfering with these peculiar tumour mitochondrial functions and will disclose novel approaches for the prevention and treatment of malignant diseases. Here, we review the peculiarity of tumour mitochondrial bioenergetics and the mode it is linked to the cell metabolism, providing a short overview of the evidence accumulated so far, but highlighting the more recent advances. This article is part of a Special Issue entitled: Bioenergetics of Cancer.►Mitochondrial hallmarks of tumor cells.►Complex I of the respiratory chain is reduced in many cancer cells.►Oligomers of F1F0ATPase are reduced in cancer cells.►Mitochondrial membranes are critical to the life or death of cancer cells.
Keywords: Mitochondria; Cancer; Oxidative phosphorylation; Ros; Apoptosis; Complex I;

A distinctive metabolic trait of tumors is their enforced aerobic glycolysis. This phenotype was first reported by Otto Warburg, who suggested that the increased glucose consumption of cancer cells under aerobic conditions might result from an impaired bioenergetic activity of their mitochondria. A central player in defining the bioenergetic activity of the cell is the mitochondrial H+-ATP synthase. The expression of its catalytic subunit β-F1-ATPase is tightly regulated at post-transcriptional levels during mammalian development and in the cell cycle. Moreover, the down-regulation of β-F1-ATPase is a hallmark of most human carcinomas. In this review we summarize our present understanding of the molecular mechanisms that participate in promoting the “abnormal” aerobic glycolysis of prevalent human carcinomas. The role of the ATPase Inhibitor Factor 1 (IF1) and of Ras-GAP SH3 binding protein 1 (G3BP1), controlling the activity of the H+-ATP synthase and the translation of β-F1-ATPase mRNA respectively in cancer cells is emphasized. Furthermore, we underline the role of mitochondrial dysfunction as a pivotal player of tumorigenesis. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Repression of the bioenergetic function of mitochondria in human tumors. ► Inhibition of oxidative phosphorylation by the ATPase Inhibitory Factor IF1 in cancer. ► Regulation of the expression of the H+-ATP synthase by RNA binding proteins. ► The tumor suppressor function of oxidative phosphorylation.
Keywords: Mitochondria; Cancer; H+-ATP synthase; Aerobic glycolysis; ATPase Inhibitory Factor 1 (IF1); Ras-GAP SH3 binding protein 1 (G3BP1);

Choosing between glycolysis and oxidative phosphorylation: A tumor's dilemma? by Caroline Jose; Nadège Bellance; Rodrigue Rossignol (552-561).
A considerable amount of knowledge has been produced during the last five years on the bioenergetics of cancer cells, leading to a better understanding of the regulation of energy metabolism during oncogenesis, or in adverse conditions of energy substrate intermittent deprivation. The general enhancement of the glycolytic machinery in various cancer cell lines is well described and recent analyses give a better view of the changes in mitochondrial oxidative phosphorylation during oncogenesis. While some studies demonstrate a reduction of oxidative phosphorylation (OXPHOS) capacity in different types of cancer cells, other investigations revealed contradictory modifications with the upregulation of OXPHOS components and a larger dependency of cancer cells on oxidative energy substrates for anabolism and energy production. This apparent conflictual picture is explained by differences in tumor size, hypoxia, and the sequence of oncogenes activated. The role of p53, C-MYC, Oct and RAS on the control of mitochondrial respiration and glutamine utilization has been explained recently on artificial models of tumorigenesis. Likewise, the generation of induced pluripotent stem cells from oncogene activation also showed the role of C-MYC and Oct in the regulation of mitochondrial biogenesis and ROS generation. In this review article we put emphasis on the description of various bioenergetic types of tumors, from exclusively glycolytic to mainly OXPHOS, and the modulation of both the metabolic apparatus and the modalities of energy substrate utilization according to tumor stage, serial oncogene activation and associated or not fluctuating microenvironmental substrate conditions. We conclude on the importance of a dynamic view of tumor bioenergetics. This article is part of a Special Issue entitled: Bioenergetics of Cancer.►The bioenergetics of cancer cells differs from normals. ►Warburg hypothesis is not verified in tumors using mitochondria to synthesize ATP. ►Different oncogenes can either switch on or switch off OXPHOS. ►Bioenergetic profiling is a prerequisite to metabolic therapy. ►Aerobic glycolysis and OXPHOS cooperate during cancer progression.
Keywords: Cancer; Bioenergetics; Oxidative phosphorylation; Mitochondrion; Oncogene;

Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism by Arnaud Chevrollier; Dominique Loiseau; Pascal Reynier; Georges Stepien (562-567).
Adenine nucleotide translocase (ANT), a mitochondrial protein that facilitates the exchange of ADP and ATP across the mitochondrial inner membrane, plays an essential role in cellular energy metabolism. Human ANT presents four isoforms (ANT1-4), each with a specific expression depending on the nature of the tissue, cell type, developmental stage and status of cell proliferation. Thus, ANT1 is specific to muscle and brain tissues; ANT2 occurs mainly in proliferative, undifferentiated cells; ANT3 is ubiquitous; and ANT4 is found in germ cells. ANT1 and ANT3 export the ATP produced by oxidative phosphorylation (OxPhos) from the mitochondria into the cytosol while importing ADP. In contrast, the expression of ANT2, which is linked to the rate of glycolytic metabolism, is an important indicator of carcinogenesis. In fact, cancers are characterized by major metabolic changes that switch cells from the normally dual oxidative and glycolytic metabolisms to an almost exclusively glycolytic metabolism. When OxPhos activity is impaired, ANT2 imports glycolytically produced ATP into the mitochondria. In the mitochondrial matrix, the F1F0-ATPase complex hydrolyzes the ATP, pumping out a proton into the intermembrane space. The reverse operations of ANT2 and F1F0-ATPase under glycolytic conditions contribute to maintaining the mitochondrial membrane potential, ensuring cell survival and proliferation. Unlike the ANT1 and ANT3 isoforms, ANT2 is not pro-apoptotic and may therefore contribute to carcinogenesis. Since the expression of ANT2 is closely linked to the mitochondrial bioenergetics of tumors, it should be taken into account for individualizing cancer treatments and for the development of anticancer strategies. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Mitochondrial adenine nucleotide translocase isoforms (ANTs) have a main role in cellular energy metabolism. ► In normal cell, ANT1 and ANT3 export OXPHOS mitochondrial ATP to the cytosol. ► In tumoral cell, aerobic glycolysis is associated with defective mitochondrial ATP production. ► Glycolytic ATP is imported into mitochondria by ANT2 to maintain the mitochondrial membrane potential (ΔΨm) and to prevent apoptosis.
Keywords: Cancer; Adenine nucleotide translocase; Mitochondria; Glycolysis;

During the last decades a considerable amount of research has been focused on cancer. Recently, tumor cell metabolism has been considered as a possible target for cancer therapy. It is widely accepted that tumors display enhanced glycolytic activity and impaired oxidative phosphorylation (Warburg effect). Therefore, it seems reasonable that disruption of glycolysis might be a promising candidate for specific anti-cancer therapy. Nevertheless, the concept of aerobic glycolysis as the paradigm of tumor cell metabolism has been challenged, as some tumor cells exhibit high rates of oxidative phosphorylation. Mitochondrial physiology in cancer cells is linked to the Warburg effect. Besides, its central role in apoptosis makes this organelle a promising “dual hit target” to selectively eliminate tumor cells. From a metabolic point of view, the fermenting yeast Saccharomyces cerevisiae and tumor cells share several features. In this paper we will review these common metabolic properties as well as the possible origins of the Crabtree and Warburg effects. This article is part of a Special Issue entitled: Bioenergetics of Cancer.►Cancer cells and fermenting yeast share several metabolic features.►The induction of the Crabtree and the Warburg effect is similar in both cell types.►Yeast metabolism is regulated by oncogene-homologues.►Yeast might be a suitable metabolic model for studies on targeting cancer metabolism.
Keywords: Energy metabolism; Warburg; Crabtree; Mitochondria; Glycolysis; Oncogene;

Metabolic management of brain cancer by Thomas N. Seyfried; Michael A. Kiebish; Jeremy Marsh; Laura M. Shelton; Leanne C. Huysentruyt; Purna Mukherjee (577-594).
Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As primarily a metabolic disease, malignant brain cancer can be managed through changes in metabolic environment. In contrast to normal neurons and glia, which readily transition to ketone bodies (β-hydroxybutyrate) for energy under reduced glucose, malignant brain tumors are strongly dependent on glycolysis for energy. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome and normal mitochondria can effectively transition from one energy state to another. Mutations restrict genomic and metabolic flexibility thus making tumor cells more vulnerable to energy stress than normal cells. We propose an alternative approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and metabolically challenged tumor cells. This approach to brain cancer management is supported from recent studies in mice and humans treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are presented for the metabolic management of brain cancer. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Most cancer, including brain cancer, is primarily a disease of energy metabolism. ► Current standards of care for brain cancer management can provoke brain cancer growth and recurrence. ► Brain tumors use glucose and glutamine as major metabolic fuels, but do not use ketone bodies. ► Non-toxic calorie restricted ketogenic diets target glucose and glutamine and are anti-angiogenic, anti-invasive, and pro-apoptotic. ► Brain cancer can be managed based on principles of evolutionary biology, metabolic control analysis, and the Warburg theory of cancer.
Keywords: Angiogenesis; Apoptosis; Invasion; Caloric restriction; Glioma; Inflammation; Ketone bodies; Metabolic control analysis; Vascularity;

Mitochondrial proteases and cancer by Anne-Laure Bulteau; Aurelien Bayot (595-601).
Mitochondria are a major source of intracellular reactive oxygen species, the production of which increases with cancer. The deleterious effects of reactive oxygen species may be responsible for the impairment of mitochondrial function observed during various pathophysiological states associated with oxidative stress and cancer. These organelles are also targets of oxidative damage (oxidation of mitochondrial DNA, lipids, protein). An important factor for protein maintenance in the presence of oxidative stress is enzymatic reversal of oxidative modifications and/or protein degradation. Failure of these processes is likely a critical component of the cancer process. Mitochondrial proteases degrade misfolded and non-assemble polypeptides, thus performing quality control surveillance in the organelle. Mitochondrial proteases may be directly involved in cancer development as recently shown for HtrA2/Omi or may regulate crucial mitochondrial molecule such as cytochrome c oxidase 4 a subunit of the cytochrome c oxidase complex degraded by the Lon protease. Thus, the role of mitochondrial proteases is further addressed in the context of oxidative stress and cancer. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Mitochondrial protein quality control by proteases is involved in cancer development. ► HtrA2 is a new target in cancer therapy. ► Prohibitins are involved in cell proliferation.
Keywords: Mitochondrial protease; Lon protease; Prohibitin; HtrA2/Omi; Cancer;

Gliomas still represent a serious and discouraging brain tumor; despite of the diversity of therapeutic modalities, the prognosis for patients is still poor. Understanding the structural and functional characteristics of the vascular microenvironment in gliomas is essential for the design of future therapeutic strategies. This review describes and analyzes the electron microscopy morphology of the mitochondrial network in human gliomas and their vascular microenvironment. Heterogeneous mitochondrial network alterations in glioma cells and in microvascular environment are implicated directly and indirectly in the processes linked to hypoxia-tolerant and hypoxia-sensitive cells phenotype, effects of the hypoxia-inducible factor-1α, increased expression of several glycolytic protein isoforms as well as fatty acid synthase, and survivin. The prevalent existence of partial or total cristolysis observed suggests that oxidative phosphorylation is severely compromised. A mixed therapy emerged as the most appropriate. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Mitochondrial network is highly heterogeneous; this fact is related with the cellular variability of astrocytomas and variations in microenvironment conditions. ► The prevalent existence of partial or total cristolysis suggests that the ability of human astrocytomas to generate ATP by mitochondrial oxidative phosphorylation would be severely compromised. ► In some astrocytoma cells, a predominant presence of mitochondria with dense matrix displayed in closed groups exists; in other, the principal finding is the lucent-swelling mitochondria with disarrangement and distortion of cristae and partial or total cristolysis. ► Mitochondria are implicated directly and indirectly in the processes linked to hypoxia-tolerant and hypoxia-sensitive cells phenotype, effects of the HIF-1α, increased expression of glycolytic protein isoforms, fatty acid synthase, and survivin, consequently a mixed therapy emerged as the most appropriate.
Keywords: Mitochondrion; Mitochondrial Network; Cancer; Glioma; Electron Microscopy;

XPC silencing in normal human keratinocytes triggers metabolic alterations through NOX-1 activation-mediated reactive oxygen species by Hamid Reza Rezvani; Rodrigue Rossignol; Nsrein Ali; Giovanni Benard; Xiuwei Tang; Hee Seung Yang; Thomas Jouary; Hubert de Verneuil; Alain Taïeb; Arianna L. Kim; Frédéric Mazurier (609-619).
Cancer cells utilize complex mechanisms to remodel their bioenergetic properties. We exploited the intrinsic genomic stability of xeroderma pigmentosum C (XPC) to understand the inter-relationships between genomic instability, reactive oxygen species (ROS) generation, and metabolic alterations during neoplastic transformation. We showed that knockdown of XPC (XPCKD) in normal human keratinocytes results in metabolism remodeling through NADPH oxidase-1 (NOX-1) activation, which in turn leads to increased ROS levels. While enforcing antioxidant defenses by overexpressing catalase, CuZnSOD, or MnSOD could not block the metabolism remodeling, impaired NOX-1 activation abrogates both alteration in ROS levels and modifications of energy metabolism. As NOX-1 activation is observed in human squamous cell carcinomas (SCCs), the blockade of NOX-1 could be a target for the prevention and the treatment of skin cancers. This article is part of a Special Issue entitled: Bioenergetics of Cancer.►XPC downregulation induces ROS generation via NOX-1 activation. ►XPC silencing triggers metabolism remodeling through the elevation of ROS level. ►Impairment of NOX-1 activation restores XPC-silencing induced metabolism remodeling. ►NOX-1 expression in SCCs is higher than healthy skin.
Keywords: Genomic stability; Warburg effect; Metabolism; ROS; XPC; NADPH oxidase; Antioxidant enzyme;

Genetic insights into OXPHOS defect and its role in cancer by Dhyan Chandra; Keshav K. Singh (620-625).
Warburg proposed that cancer originates from irreversible injury to mitochondrial oxidative phosphorylation (mtOXPHOS), which leads to an increase rate of aerobic glycolysis in most cancers. However, despite several decades of research related to Warburg effect, very little is known about the underlying genetic cause(s) of mtOXPHOS impairment in cancers. Proteins that participate in mtOXPHOS are encoded by both mitochondrial DNA (mtDNA) as well as nuclear DNA. This review describes mutations in mtDNA and reduced mtDNA copy number, which contribute to OXPHOS defects in cancer cells. Maternally inherited mtDNA renders susceptibility to cancer, and mutation in the nuclear encoded genes causes defects in mtOXPHOS system. Mitochondria damage checkpoint (mitocheckpoint) induces epigenomic changes in the nucleus, which can reverse injury to OXPHOS. However, irreversible injury to OXPHOS can lead to persistent mitochondrial dysfunction inducing genetic instability in the nuclear genome. Together, we propose that “mitocheckpoint” led epigenomic and genomic changes must play a key role in reversible and irreversible injury to OXPHOS described by Warburg. These epigenetic and genetic changes underlie the Warburg phenotype, which contributes to the development of cancer. This article is part of a Special Issue entitled: Bioenergetics of Cancer.►Injury to OXPHOS induces mitocheckpoint response. ►Mitocheckpoint regulates reversible epigenomic changes in the nucleus. ►Irreversible injury to OXPHOS induces genetic instability in the nuclear genome. ►Defective OXPHOS-induced epigenetic/genetic changes may lead to development of cancer.
Keywords: OXPHOS defect; Cancer; Warburg effect; Mitocheckpoint; Epigenetic; Epigenetics; Epigenomis; Mitochondria; Genetic instability; Chromosomal instability; mtDNA;

Hit proteins, mitochondria and cancer by Juliette Martin; Marie V. St-Pierre; Jean-François Dufour (626-632).
The histidine triad (HIT) superfamily comprises proteins that share the histidine triad motif, His-ϕ-His-ϕ-His-ϕ–ϕ, where ϕ is a hydrophobic amino acid. HIT proteins are ubiquitous in prokaryotes and eukaryotes. HIT proteins bind nucleotides and exert dinucleotidyl hydrolase, nucleotidylyl transferase or phosphoramidate hydrolase enzymatic activity. In humans, 5 families of HIT proteins are recognized. The accumulated epidemiological and experimental evidence indicates that two branches of the superfamily, the HINT (Histidine Triad Nucleotide Binding) members and FHIT (Fragile Histidine Triad), have tumor suppressor properties but a conclusive physiological role can still not be assigned to these proteins. Aprataxin forms another discrete branch of the HIT superfamily, is implicated in DNA repair mechanisms and unlike the HINT and FHIT members, a defective protein can be conclusively linked to a disease, ataxia with oculomotor apraxia type 1. The scavenger mRNA decapping enzyme, DcpS, forms a fourth branch of the HIT superfamily. Finally, the GalT enzymes, which exert specific nucleoside monophosphate transferase activity, form a fifth branch that is not implicated in tumorigenesis. The molecular mechanisms by which the HINT and FHIT proteins participate in bioenergetics of cancer are just beginning to be unraveled. Their purported actions as tumor suppressors are highlighted in this review. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► HIT proteins are characterized by a histidine triad nucleotide binding domain. ► Humans have 7 HIT proteins. ► FHIT is located at the most fragile site of the genome and is frequently disrupted in cancers. ► HINT1 is a tumor suppressor. ► HINT2 is the only mitochondrial HIT protein; it is down-regulated in hepatocellular carcinoma of poor prognosis.
Keywords: HIT domain; Hint proteins; Fhit; Aprataxin; Apoptosis; Mitochondria;

Learning from oncocytic tumors: Why choose inefficient mitochondria? by Giuseppe Gasparre; Giovanni Romeo; Michela Rugolo; Anna Maria Porcelli (633-642).
A prominent role for mitochondrial genes and metabolism has been recently characterized in oncocytic transformation of cancer cells. From mitochondrial ultrastructure alterations to respiratory complexes disruption and mutations within mitochondrial genes, oncocytic tumors present with a plethora of features that have helped understand the role that these organelles and their fundamental metabolic functions may play in cancer development. The history of this under-diagnosed subset of tumors and the bioenergetic implications of their mitochondrial derangement are discussed in this review along with the opportunities that oncocytic tumors offer to draw general conclusions on the involvement of mitochondria in cancer. This article is part of a Special Issue entitled: Bioenergetics of Cancer.
Keywords: Oncocytic tumors; Mitochondria; mtDNA mutations; Complex I; Heteroplasmy; Hypoxia-inducible factor 1-alpha;

Maternally inherited susceptibility to cancer by María Pilar Bayona-Bafaluy; Ester López-Gallardo; Julio Montoya; Eduardo Ruiz-Pesini (643-649).
Tumor microenvironment promotes mtDNA mutations. A number of these mutations will affect cell metabolism and increase cell survival. These mutations are positively selected and contribute to other tumor features, such as extracellular matrix remodeling and angiogenic processes, thus favoring metastases. Like somatic mutations, although with less marked effects, some mtDNA population polymorphisms will affect OXPHOS function, cell metabolism, and homeostasis. Thus, they could behave as inherited susceptibility factors for cancer. However, in addition to epidemiological evidence, other more direct clues are required. The cybrid approach can help to clarify this issue. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Tumor microenvironment promotes mtDNA mutations. ► Some mtDNA mutations can contribute to tumor features. ► Many tumor mtDNA mutations have been found as haplogroup-defining polymorphisms. ► MtDNA polymorphisms could behave as inherited susceptibility factors for cancer. ► Cybrids can be used to check the effect of cancer-associated mtDNA polymorphisms.
Keywords: mtDNA; Cancer; Cybrid;

Metabolomics for mitochondrial and cancer studies by Deepak Nagrath; Christine Caneba; Thasni Karedath; Nadege Bellance (650-663).
Metabolomics, a high-throughput global metabolite analysis, is a burgeoning field, and in recent times has shown substantial evidence to support its emerging role in cancer diagnosis, cancer recurrence, and prognosis, as well as its impact in identifying novel cancer biomarkers and developing cancer therapeutics. Newly evolving advances in disease diagnostics and therapy will further facilitate future growth in the field of metabolomics, especially in cancer, where there is a dire need for sensitive and more affordable diagnostic tools and an urgency to develop effective therapies and identify reliable biomarkers to predict accurately the response to a therapy. Here, we review the application of metabolomics in cancer and mitochondrial studies and its role in enabling the understanding of altered metabolism and malignant transformation during cancer growth and metastasis. The recent developments in the area of metabolic flux analysis may help to close the gap between clinical metabolomics research and the development of cancer metabolome. In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and yet sensitive biomarkers both to track the disease and to develop and evolve therapies during the course of treatment. Recent advances in metabolomics along with the novel strategies to analyze, understand, and construct the metabolic pathways opens this window of opportunity in a very cost-effective manner. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Metabolomics is used to assess mitochondrial function and metabolism in cancer. ► common NMR and MS techniques are used to characterize metabolites in cancer. ► Techniques can identify in urine, blood, and saliva from cancer patients. ► metabolic flux analysis is a new metabolomics tool for studying cancer metabolism.
Keywords: Metabolomics; Cancer metabolism; Mitochondrial bioenergetics; Metabolic footprinting; Metabolic profiling;

Role of obesity-associated dysfunctional adipose tissue in cancer: A molecular nutrition approach by Pedro L. Prieto-Hontoria; Patricia Pérez-Matute; Marta Fernández-Galilea; Matilde Bustos; J. Alfredo Martínez; María J. Moreno-Aliaga (664-678).
Obesity is a complex disease caused by the interaction of a myriad of genetic, dietary, lifestyle and environmental factors, which favors a chronic positive energy balance, leading to increased body fat mass. There is emerging evidence of a strong association between obesity and an increased risk of cancer. However, the mechanisms linking both diseases are not fully understood. Here, we analyze the current knowledge about the potential contribution that expanding adipose tissue in obesity could make to the development of cancer via dysregulated secretion of pro-inflammatory cytokines, chemokines and adipokines such as TNF-α, IL-6, leptin, adiponectin, visfatin and PAI-1. Dietary factors play an important role in the risk of suffering obesity and cancer. The identification of bioactive dietary factors or substances that affect some of the components of energy balance to prevent/reduce weight gain as well as cancer is a promising avenue of research. This article reviews the beneficial effects of some bioactive food molecules (n-3 PUFA, CLA, resveratrol and lipoic acid) in energy metabolism and cancer, focusing on the molecular mechanisms involved, which may provide new therapeutic targets in obesity and cancer. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► The relationship between obesity and increased risk of cancer is reviewed. ► Obesity-associated dysfunctional adipose tissue plays a role in cancer. ► Obesity, adipose tissue dysfunction and cancer can be triggered by adverse nutrition. ► Dietary bioactive food components may prevent adipose tissue failure and cancer. ► Nutrigenomics allows understanding how dietary factors affect obesity and cancer.
Keywords: Obesity; Cancer; Adipose tissue; Adipokine; Nutrigenomics; Dietary bioactive factor; Mitochondrial biogenesis;

Microtubule-targeted agents: When mitochondria become essential to chemotherapy by A. Rovini; A. Savry; D. Braguer; M. Carré (679-688).
Microtubule-Targeting Agents (MTAs) constitute a class of drugs largely used for cancer treatment in adults and children. In cancer cells, they suppress microtubule dynamics, and induce cell death via the mitochondrial intrinsic pathway. To date, links between mitochondria and microtubule network disturbance in MTAs mechanism of action are not obvious. The aim of the present contribution is to provide elements that could answer to the question: how far are mitochondria essential to anticancer chemotherapy that targets the microtubule cytoskeleton? We review the main molecular candidates to link microtubule alteration with the apoptotic mitochondrial pathway control. Involvement of direct targeting of mitochondria in MTA efficacy is also discussed. Furthermore, we line up current evidence and emerging concepts on the participation of both mitochondria and microtubule in MTA neurotoxic side effects. To decipher the interconnections between the mitochondrial and the microtubule networks may help to improve cancer cell response to chemotherapy. This article is part of a Special Issue entitled: Bioenergetics of Cancer.►Microtubule-Targeting Agents (MTAs) are largely used for cancer treatment. ►They suppress microtubule dynamics and initiate the apoptotic mitochondrial pathway. ►Here we review how far mitochondria are essential to anticancer chemotherapy. ►We also discussed links between mitochondria and microtubule network disturbances. ►Deciphering these two network interconnections may favor response to chemotherapy.
Keywords: Anticancer drug; Microtubule; Mitochondria; Apoptosis; Pharmacology;

Approaches for targeting mitochondria in cancer therapy by Gerard G.M. D'Souza; Mayura A Wagle; Vaibhav Saxena; Anee Shah (689-696).
The recognition of the role that mitochondria play in human health and disease is evidenced by the emergence in recent decades of a whole new field of “Mitochondrial Medicine”. Molecules located on or inside mitochondria are considered prime pharmacological targets and a wide range of efforts are underway to exploit these targets to develop targeted therapies for various diseases including cancer. However the concept of targeting, while seemingly simple in theory, has multiple subtly different practical approaches. The focus of this article is to highlight these differences in the context of a discussion on the current status of various mitochondria-targeted approaches to cancer therapy. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Mitochondria have emerged as a major target for anticancer therapy. ► Drugs may be designed for selective action on mitochondrial targets. ► Drugs may be structurally modified to increase their accumulation in the mitochondria. ► Nanocarriers may mediate increased drug accumulation in the mitochondria.
Keywords: Mitochondrion; Targeting; Cancer; Nanocarrier; Subcellular; Delivery;

Bioactive food components, cancer cell growth limitation and reversal of glycolytic metabolism by Jaap Keijer; Melissa Bekkenkamp-Grovenstein; Dini Venema; Yvonne E.M. Dommels (697-706).
Cancer cells are resistant to apoptosis and show a shift in energy production from mitochondrial oxidative phosphorylation to cytosolic glycolysis. Apoptosis resistance and metabolic reprogramming are linked in many cancer cells and both processes center on mitochondria. Clearly, mutated cancer cells escape surveillance and turn into selfish cells. However, many of the mechanisms that operate cellular metabolic control still function in cancer cells. This review describes the metabolic importance of glucose and glutamine, glycolytic enzymes, oxygen, growth cofactors and mitochondria and focuses on the potential role of bioactive food components, including micronutrients. The role of B- and A-vitamin cofactors in (mitochondrial) metabolism is highlighted and the cancer protective potential of omega-3 fatty acids and several polyphenols is discussed in relation to metabolic reprogramming, including the mechanisms that may be involved. Furthermore, it is shown that cancer cell growth reduction by limiting the growth cofactor folic acid seems to be associated with reversal of metabolic reprogramming. Altogether, reversal of metabolic reprogramming may be an attractive strategy to increase susceptibility to apoptotic surveillance. Food bioactive components that affect various aspects of metabolism may be important tools to reverse glycolytic to oxidative metabolism and enhance sensitivity to apoptosis. The success of such a strategy may depend on several actors, acting in concert. Growth cofactors may be one of these, which call for careful (re)evaluation of their function in normal and in cancer metabolism. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Cancer cell energy metabolism provides targets for anti-cancer therapy. ► In cancer cells, homeostatic mechanisms are altered, but not absent. ► Bioactive food components can support metabolic reprogramming. ► Growth cofactors should be considered as part of an anti-cancer strategy.
Keywords: Nutrition; Folate; Mitochondria; Metabolic reprogramming; B-vitamin; Energy metabolism;

AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation by Caroline Jose; Etienne Hébert-Chatelain; Nadège Bellance; Anaïs Larendra; Melser Su; Karine Nouette-Gaulain; Rodrigue Rossignol (707-718).
The AMP-activated protein kinase agonist AICAR mimics a low intracellular energy state and inhibits the proliferation of cancer cells by different mechanisms, which may depend on the bioenergetic signature of these cells. AICAR can also stimulate mitochondrial biogenesis in myoblasts, neurons and HeLa cells. Yet, whether the reactivation of oxidative phosphorylation biogenesis by AICAR contributes to the growth arrest of cancer cells remains undetermined. To investigate this possibility, we looked at the impact of 24- and 48-hour treatments with 750 μM AICAR on human cancer cell lines (HeLa, DU145, and HEPG2), non-cancer cells (EM64, FM14, and HLF), embryonic cells (MRC5) and Rho0 cells. We determined the bioenergetic profile of these cells and assessed the effect of AICAR on oxidative phosphorylation biogenesis, cell viability and cell proliferation, ROS generation, mitochondrial membrane potential and apoptosis induction. We also followed possible changes in metabolic regulators such as Akt and Hif1-α stabilization which might participate to the anti-proliferative effect of AICAR. Our results demonstrated a strong and cancer-specific anti-growth effect of AICAR that may be explained by three different modes according to cell type: the first mode included stimulation of the mitochondrial apoptotic pathway however with compensatory activation of Akt and upregulation of oxidative phosphorylation. In the second mode of action of AICAR Akt phosphorylation was reduced. In the third mode of action, apoptosis was activated by different pathways. The sensitivity to AICAR was higher in cells with a low steady-state ATP content and a high proliferation rate. This article is part of a Special Issue entitled: Bioenergetics of Cancer.Display Omitted►The bioenergetic properties of tumors differ from normal tissue ones. ►Cancer cells are adapted to grow under hypoxia and aglycemia. ►The blockade of cancer cell's energy production could limit tumor growth. ►AICAR inhibits specifically cancer cell growth. ►Three Cell type dependent modes of action of AICAR were observed.
Keywords: Tumor; Mitochondrion; Oxidative phosphorylation; AICAR;

Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia by Karin Eberhart; Johannes Rainer; Daniel Bindreither; Ireen Ritter; Erich Gnaiger; Reinhard Kofler; Peter J. Oefner; Kathrin Renner (719-725).
Mitochondria are signal-integrating organelles involved in cell death induction. Mitochondrial alterations and reduction in energy metabolism have been previously reported in the context of glucocorticoid (GC)-triggered apoptosis, although the mechanism is not yet clarified. We analyzed mitochondrial function in a GC-sensitive precursor B-cell acute lymphoblastic leukemia (ALL) model as well as in GC-sensitive and GC-resistant T-ALL model systems. Respiratory activity was preserved in intact GC-sensitive cells up to 24 h under treatment with 100 nM dexamethasone before depression of mitochondrial respiration occurred. Severe repression of mitochondrial respiratory function was observed after permeabilization of the cell membrane and provision of exogenous substrates. Several mitochondrial metabolite and protein transporters and two subunits of the ATP synthase were downregulated in the T-ALL and in the precursor B-ALL model at the gene expression level under dexamethasone treatment. These data could partly be confirmed in ALL lymphoblasts from patients, dependent on the molecular abnormality in the ALL cells. GC-resistant cell lines did not show any of these defects after dexamethasone treatment. In conclusion, in GC-sensitive ALL cells, dexamethasone induces changes in membrane properties that together with the reduced expression of mitochondrial transporters of substrates and proteins may lead to repressed mitochondrial respiratory activity and lower ATP levels that contribute to GC-induced apoptosis. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Dexamethasone changed mitochondrial membrane properties in model systems of childhood leukemia. ► Dexamethasone treatment reduced mitochondrial routine respiration and ETS capacity. ► Dexamethasone induced a downregulation of mitochondrial translocases in the model systems and patients. ► In resistant cells, dexamethasone did not induce any mitochondrial alterations.
Keywords: Glucocorticoid; Acute lymphoblastic leukemia; Mitochondrial transport; Mitochondrial membrane properties; Mitochondrial respiration; Apoptosis;

Normal differentiated cells rely primarily on mitochondrial oxidative phosphorylation to produce adenosine triphosphate (ATP) to maintain their viability and functions by using three major bioenergetic fuels: glucose, glutamine and fatty acids. Many cancer cells, however, rely on aerobic glycolysis for their growth and survival, and recent studies indicate that some cancer cells depend on glutamine as well. This altered metabolism in cancers occurs through oncogene activation or loss of tumor suppressor genes in multiple signaling pathways, including the phosphoinositide 3-kinase and Myc pathways. Relatively little is known, however, about the role of fatty acids as a bioenergetic fuel in growth and survival of cancer cells. Here, we report that human glioblastoma SF188 cells oxidize fatty acids and that inhibition of fatty acid β-oxidation by etomoxir, a carnitine palmitoyltransferase 1 inhibitor, markedly reduces cellular ATP levels and viability. We also found that inhibition of fatty acid oxidation decreases nicotinamide adenine dinucleotide phosphate (NADPH) levels and the reduced glutathione (GSH) content and elevates intracellular reactive oxygen species. These results suggest that modulation of fatty acid oxidation controls the NADPH level. In the presence of reactive oxygen species scavenger tiron, however, ATP depletion is prevented without restoring fatty acid oxidation. This suggests that oxidative stress may lead to bioenergetic failure and cell death. Our work provides evidence that mitochondrial fatty acid oxidation may provide NADPH for defense against oxidative stress and prevent ATP loss and cell death. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Cancer cells can oxidize endogenous and exogenous fatty acids. ► Endogenous fatty acids can be synthesized from L-glutamine in glioblastoma cells. ► Inhibition of fatty acid oxidation by CPT-1 inhibitor etomoxir in SF188 glioblastoma cells causes ATP depletion and cell death. ► Inhibition of fatty acid oxidation by etomoxir decreases NADPH and increases ROS levels.
Keywords: Fatty acid oxidation; NADPH; ROS; Oxidative stress; Mitochondrial dysfunction;

Recent advances in apoptosis, mitochondria and drug resistance in cancer cells by Inthrani R. Indran; Grégory Tufo; Shazib Pervaiz; Catherine Brenner (735-745).
Defective or inefficient apoptosis is an acquired hallmark of cancer cells. Thus, a thorough understanding of apoptotic signaling pathways and insights into apoptosis resistance mechanisms are imperative to unravel novel drug targets for the design of more effective and target selective therapeutic strategies. This review aims at providing an overview of the recent understanding of apoptotic signaling pathways, the main mechanisms by which cancer cells resist apoptotic insults, and discusses some recent attempts to target the mitochondrion for restoring efficient cell death signaling in cancer cells. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Mitochondria are involved in apoptosis. ► Hallmarks of cancer cells include their resistance to apoptosis and their mitochondrial dysfunction. ► Targeting the mitochondria to sensitize cancer cells to apoptosis is a major aim in anti-cancer therapy.
Keywords: Mitochondrion; Oncogene; Bcl-2; Permeability transition pore; Cell death; Metabolism;

Carbon metabolism and the sign of control coefficients in metabolic adaptations underlying K-ras transformation by Pedro de Atauri; Adrian Benito; Pedro Vizán; Miriam Zanuy; Ramón Mangues; Silvia Marín; Marta Cascante (746-754).
Metabolic adaptations are associated with changes in enzyme activities. These adaptations are characterized by patterns of positive and negative changes in metabolic fluxes and concentrations of intermediate metabolites. Knowledge of the mechanism and parameters governing enzyme kinetics is rarely available. However, the signs—increases or decreases—of many of these changes can be predicted using the signs of metabolic control coefficients. These signs require the only knowledge of the structure of the metabolic network and a limited qualitative knowledge of the regulatory dependences, which is widely available for carbon metabolism. Here, as a case study, we identified control coefficients with fixed signs in order to predict the pattern of changes in key enzyme activities which can explain the observed changes in fluxes and concentrations underlying the metabolic adaptations in oncogenic K-ras transformation in NIH-3T3 cells. The fixed signs of control coefficients indicate that metabolic changes following the oncogenic transformation—increased glycolysis and oxidative branch of the pentose-phosphate pathway, and decreased concentration in sugar-phosphates—could be associated with increases in activity for glucose-6-phosphate dehydrogenase, pyruvate kinase and lactate dehydrogenase, and decrease for transketolase. These predictions were validated experimentally by measuring specific activities. We conclude that predictions based on fixed signs of control coefficients are a very robust tool for the identification of changes in enzyme activities that can explain observed metabolic adaptations in carbon metabolism. This article is part of a Special Issue entitled: Bioenergetics of Cancer.► Metabolic adaptation in oncogenic K-ras transformation in NIH-3T3 cells. ► Identification of control coefficients with fixed signs. ► Fixed-sign control coefficients to identify enzymes leading to metabolic adaptation.
Keywords: Metabolic control analysis; Control coefficient signs; Carbon metabolism; K-Ras cell transformation;

Modeling cancer glycolysis by Alvaro Marín-Hernández; Juan Carlos Gallardo-Pérez; Sara Rodríguez-Enríquez; Rusely Encalada; Rafael Moreno-Sánchez; Emma Saavedra (755-767).
Most cancer cells exhibit an accelerated glycolysis rate compared to normal cells. This metabolic change is associated with the over-expression of all the pathway enzymes and transporters (as induced by HIF-1α and other oncogenes), and with the expression of hexokinase (HK) and phosphofructokinase type 1 (PFK-1) isoenzymes with different regulatory properties. Hence, a control distribution of tumor glycolysis, modified from that observed in normal cells, can be expected. To define the control distribution and to understand the underlying control mechanisms, kinetic models of glycolysis of rodent AS-30D hepatoma and human cervix HeLa cells were constructed with experimental data obtained here for each pathway step (enzyme kinetics; steady-state pathway metabolite concentrations and fluxes). The models predicted with high accuracy the fluxes and metabolite concentrations found in living cancer cells under physiological O2 and glucose concentrations as well as under hypoxic and hypoglycemic conditions prevailing during tumor progression. The results indicated that HK ≥ HPI > GLUT in AS-30D whereas glycogen degradation ≥ GLUT > HK in HeLa were the main flux- and ATP concentration-control steps. Modeling also revealed that, in order to diminish the glycolytic flux or the ATP concentration by 50%, it was required to decrease GLUT or HK or HPI by 76% (AS-30D), and GLUT or glycogen degradation by 87–99% (HeLa), or decreasing simultaneously the mentioned steps by 47%. Thus, these proteins are proposed to be the foremost therapeutic targets because their simultaneous inhibition will have greater antagonistic effects on tumor energy metabolism than inhibition of all other glycolytic, non-controlling, enzymes. This article is part of a Special Issue entitled Bioenergetics of Cancer.► The glycolytic pathway of both AS-30D hepatoma and cervix HeLa cells was modeled. ► In vitro enzyme kinetics and in vivo metabolite concentrations and fluxes were used for modeling. ► The models accurately predicted the in vivo pathway behavior under different O2 and glucose physiological concentrations. ► HK > HPI > GLUT in AS-30D hepatoma and glycogen degradation > GLUT > HK in HeLa carcinoma controlled glycolysis. ► To decrease glycolytic flux or ATP by 50%, the three controlling steps have to be simultaneously diminished by 47%.
Keywords: Metabolic control analysis; Flux-control coefficient; Hexokinase; Phosphofructokinase type 1; Glucose transporter; Combined therapy;