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Research paper on oxidative phosphorylation

research paper on oxidative phosphorylation

Volume 1807, Issue 6, June 2011, Pages 534–542

Bioenergetics of Cancer

Edited By Rodrigue Rossignol


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.

Research Highlights

►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.


  • HIF-1, hypoxia-inducible factor 1;
  • HIFs, hypoxia-inducible factors;
  • IF1, ATP synthase natural inhibitor protein;
  • F1F0-ATPase, ATP synthase or Complex V;
  • COX, cytochrome c oxidase or Complex IV;
  • Complex III, ubiquinone cytochrome c oxidoreductase;
  • ΔΨm, electrical membrane potential of mitochondria;
  • mtDNA, mitochondrial DNA;
  • AMPK, AMP-activated protein kinase;
  • oxphos, oxidative phosphorylation;
  • ROS, reactive oxygen species;
  • PDH, pyruvate dehydrogenase;
  • LDH, lactate dehydrogenase;
  • HK-II, hexokinase II;
  • ANT, adenine nucleotide translocator;
  • VDAC, voltage-dependent anion channel;
  • MPTP, mitochondrial permeability transition pore;
  • CyP-D, cyclophilin D;
  • UCP, uncoupling protein;
  • SDH, succinate dehydrogenase;
  • FH, fumarate hydratase;
  • Bcl2, B cell lymphoma gene-2;
  • P53, tumour protein 53;
  • c-MYC, MYC protein gene;
  • ras, gene coding a family of ras proteins;
  • PI3K, phosphatidylinositol 3-kinases;
  • AKT, protein kinases B;
  • mTOR, the mammalian target of rapamycin, serine/threonine protein kinase;
  • ERK, extracellular-signal-regulated kinases;
  • STAT3, signal transducer and activator of transcription 3, is a transcription factor which in humans is encoded by the STAT3 gene


  • Mitochondria;
  • Cancer;
  • Oxidative phosphorylation;
  • Ros;
  • Apoptosis;
  • Complex I

1. Introduction

Mitochondria are essential organelles and key integrators of metabolism, but they also play vital roles in cell death and cell signaling pathways critically influencing cell fate decisions [1]; [2] ; [3]. Mammalian mitochondria contain their own DNA (mtDNA), which encodes 13 polypeptides of oxidative phosphorylation complexes, 12S and 16S rRNAs, and 22 tRNAs required for mitochondrial function [4]. In order to synthesize ATP through oxidative phosphorylation (oxphos), mitochondria consume most of the cellular oxygen and produce the majority of reactive oxygen species (ROS) as by-products [5]. ROS have been implicated in the etiology of carcinogenesis via oxidative damage to cell macromolecules and through modulation of mitogenic signaling pathways [6]; [7] ; [8]. In addition, a number of mitochondrial dysfunctions of genetic origin are implicated in a range of age-related diseases, including tumours [9]. How mitochondrial functions are associated with cancer is a crucial and complex issue in biomedicine that is still unravelled [10] ; [11], but it warrants an extraordinary importance since mitochondria play a major role not only as energy suppliers and ROS “regulators”, but also because of their control on cellular life and death. This is of particular relevance since tumour cells can acquire resistance to apoptosis by a number of mechanisms, including mitochondrial dysfunction, the expression of anti-apoptotic proteins or by the down-regulation or mutation of pro-apoptotic proteins [12].

Cancer cells must adapt their metabolism to produce all molecules and energy required to promote tumour growth and to possibly modify their environment to survive. These metabolic peculiarities of cancer cells are recognized to be the outcome of mutations in oncogenes and tumour suppressor genes which regulate cellular metabolism. Mutations in genes including P53, RAS, c-MYC, phosphoinosine 3-phosphate kinase (PI3K), and mTOR can directly or through signaling pathways affect metabolic pathways in cancer cells as discussed in several recent reviews [13]; [14]; [15]; [16] ; [17]. Cancer cells harboring the genetic mutations are also able to thrive in adverse environments such as hypoxia inducing adaptive metabolic alterations which include glycolysis up-regulation and angiogenesis factor release [18] ; [19]. In response to hypoxia, hypoxia-induced factor 1 (HIF-1) [20], a transcription factor, is up-regulated, which enhances expression of glycolytic enzymes and concurrently it down regulates mitochondrial respiration through up-regulation of pyruvate dehydrogenase kinase 1 (PDK1) (see recent reviews [21] ; [22]). However, several tumours have been reported to display high HIF-1 activity even in normoxic condition, now referred to as pseudohypoxia [23]; [24] ; [25]. In addition, not only solid tumours present a changed metabolism with respect to matched normal tissues, hematological cell malignancies also are characterized by peculiar metabolisms, in which changes of mitochondrial functions are significant [26]; [27] ; [28], therefore indicating a pivotal role of mitochondria in tumours independently from oxygen availability.

Collectively, actual data show a great heterogeneity of metabolism changes in cancer cells, therefore comprehensive cellular and molecular basis for the association of mitochondrial bioenergetics with tumours is still undefined, despite the numerous studies carried out. This review briefly revisits the data which are accumulating to account for this association and highlights the more recent advances, particularly focusing on the metabolic and structural changes of mitochondria.

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