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Mitochondrial Respiratory Chain Complexes: Apoptosis Sensors Mutated in Cancer

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Mitochondrial Respiratory Chain Complexes: Apoptosis Sensors Mutated in Cancer Oncogene (2011) 30, 3985–4003 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer A Lemarie1,2 and S Grimm3 1INSERM U1037–Cancer Research Center of Toulouse (CRCT), Department of Experimental Therapeutics, Institut Claudius Regaud, Toulouse, France; 2Faculte´ des Sciences Pharmaceutiques, Universite´ Toulouse III, Toulouse, France and 3Department of Experimental Medicine and Toxicology, Imperial College London, Hammersmith Campus, London, UK Mutations in cancer cells affecting subunits of the Of note, electron leakage can arise all along the RC and respiratory chain (RC) indicate a central role of oxidative lead to reactive oxygen species (ROS) formation phosphorylation for tumourigenesis. Recent studies have (Figure 1). suggested that such mutations of RC complexes impact Deficiencies in the RC are frequently found in cancer apoptosis induction. We review here the evidence for cells. Among the various causes are numerous mutations this hypothesis, which in particular emerged from work in the mitochondrial genome (mtDNA) affecting sub- on how complex I and II mediate signals for apoptosis. units in RCC I, III and IV (Polyak et al., 1998; Ishikawa Both protein aggregates are specifically inhibited for et al., 2008), and in nuclear-coded components of apoptosis induction through different means by exploiting complex II (Baysal et al., 2000; Bayley et al., 2005; with protease activation and pH change, two widespread Hensen and Bayley, 2011) whose assembly factors are but independent features of dying cells. Nevertheless, likewise mutated (Ghezzi et al., 2009; Hao et al., 2009). both converge on forming reactive oxygen species for These alterations lead to specific defects of the the demise of the cell. Investigations into these mito- respiratory chain, which are described in detail below chondrial processes will remain a rewarding area for and depicted in Figure 2. Equally important for RC unravelling the causes of tumourigenesis and for discover- inhibition is the global metabolic shift from OxPhos to ing interference options. glycolysis (Gatenby and Gillies, 2004; Pelicano et al., Oncogene (2011) 30, 3985–4003; doi:10.1038/onc.2011.167; 2006), notably in hypoxia during the early stages of published online 30 May 2011 tumourigenesis (Papandreou et al., 2006; Gogvadze et al., 2010). Keywords: apoptosis; respiratory chain; reactive oxygen species; mitochondria MtDNA mutations in cancer affecting RCC I, III and IV Most RCCs are multimeric enzyme aggregates com- posed of several mtDNA- and nuclear-encoded proteins Respiratory chain defects in cancer (Figure 1). MtDNA-derived subunits of RCC I (7/45 subunits: NADH dehydrogenase subunits ND1 to ND6 The mitochondrial respiratory chain (RC) consists, as and ND4L), III (1/11 subunits: cytochrome b) and IV detailed in Figure 1, of four membrane-bound, multi- (3/13 subunits, cytochrome c oxidase subunits COXI to meric RC complexes (RCCs) and catalyzes the oxidation III) have been found altered in various types of cancers of reducing equivalents, mainly nicotinamide adenine (Brandon et al., 2006; Lu et al., 2009), although they, dinucleotide (NADH), using the terminal electron like their nuclear-encoded counterparts, can also lead acceptor oxygen (O2) in the inner mitochondrial to neurodevelopmental impairment, neurodegenerative membrane (IMM) (Lenaz and Genova, 2010). The diseases or cardiomyopathies when mutated (Benit electron transfer mediated by the RC is connected to the et al., 2009; Distelmaier et al., 2009; Diaz, 2010; final complex, ATP synthase (complex V), which Schapira, 2010). Consequently, the actual contribution generates ATP. This coupling between RC and ATP of these mutations to tumourigenesis is an important synthesis is called oxidative phosphorylation (OxPhos). question—do these mutations act as a significant cause or do they merely constitute a side effect of tumour Correspondence: Dr A Lemarie, INSERM U1037–CRCT, Department development, caused by, for example, the combined of Experimental Therapeutics, Institut Claudius Regaud, Universite´ effect of the intrinsic oxidative stress in cancer cells Toulouse III, 20-24 rue du Pont Saint Pierre, 31052 Toulouse Cedex, France. (Pelicano et al., 2004; Gogvadze et al., 2010) and the low E-mail: [email protected] or Professor S Grimm DNA repair capacity for mtDNA (Penta et al., 2001)? Department of Experimental Medicine and Toxicology, Imperial A confounding factor is the multiplicity of the mtDNA, College London, Hammersmith Campus, Du Cane Road, London which is present in these organelles in hundreds of W12 0NN, UK. E-mail: [email protected] copies. Sequencing of the mtDNA revealed hetero- Received 4 February 2011; revised and accepted 5 April 2011; published plasmy between normal and cancer cells (He et al., online 30 May 2011 2010). Few papers have so far described the precise Respiratory chain complexes and apoptosis A Lemarie and S Grimm 3986 Figure 1 Representation of the mitochondrial respiratory chain complexes and the oxidative phosphorylation system. The four complexes of the respiratory chain and the ATP synthase are schematized and the electron/proton pathways along these complexes are indicated. RCC I and II are the two main entries of reducing equivalents in the RC. RCC I (NADH:ubiquinone oxidoreductase) receives electrons from NADH and transfers them from a flavin mononucleotide (FMN) cofactor to the eight RCC I-embedded iron– sulphur (Fe-S) clusters to eventually reduce ubiquinone (coenzyme Q (CoQ or Q)) to ubiquinol (QH2) in the IMM. This reaction is coupled to the translocation of protons across the IMM from the matrix into the intermembrane space (IMS). RCC II (succinate:ubiquinone oxidoreductase) also contributes to the QH2 pool via the transfer of electrons from succinate, a tricarboxylic acid (TCA) cycle intermediate, to the complex II-embedded cofactor FAD and then to several Fe-S clusters. QH2 transfers its electrons to RCC III (ubiquinol:cytochrome c oxidoreductase) through two heme centres (cytochromes b and c1) and one Fe-S cluster. The energy generated by the electrons carried by RCC III likewise induces a translocation of protons across the IMM. Finally, RCC III delivers its electrons to cytochrome c (Cyt C), which transfers them to RCC IV (cytochrome c oxidase). This terminal RCC possesses four redox centres (two copper atoms and two cytochromes a and a3) and uses the energy generated by the electron transfer to translocate protons but also to reduce O2 in H2O at the matrix side (Belevich and Verkhovsky, 2008; Lenaz and Genova, 2010). All along the RC, electron leakage can arise and lead to reactive oxygen species (ROS) formation. The main sites for these ROS ‘hot spots’ are RCC I and III, but also RCC II (Lenaz and Genova, 2010), as indicated in the figure. The electron transfer is then coupled to the final complex, ATP synthase (complex V), which uses the protomotive force created by RCC I, III and IV to generate ATP at the matrix side. This coupling between RC and ATP synthesis is called oxidative phosphorylation (OxPhos). The number of mitochondrial DNA (mtDNA)- and nuclear DNA (nDNA)-coded subunits of each complex are also indicated. Oncogene Respiratory chain complexes and apoptosis A Lemarie and S Grimm 3987 Figure 2 Mutations of the respiratory chain components in cancer. The four complexes of the respiratory chain are schematized and the various mutations found in cancer cells that impact RC complex subunits and assembly factors are highlighted: ND1-6 and ND4L (nicotinamide adenine dinucleotide (NADH) dehydrogenase subunits 1–6 and 4L); SDHA–D (succinate dehydrogenase subunits A–D), SDHAF2 (SDH assembly factor 2); cytochrome b; COXI–III (cytochrome c oxidase subunits I–III). mechanisms of how mtDNA mutations are linked to further confirmed through the method of transmito- tumourigenesis and what consequence they have on RC chondrial cybrids (Ohta, 2006), in which mitochondria functions. Only recently have different groups supported from tumour cells are transferred into normal cells and the likelihood of a causative effect on tumour progres- allow study the mtDNA mutations independently of sion. In thyroid cancer cell lines (Abu-Amero et al., the tumoral nuclear DNA. Using this technique, it was 2005) and renal oncocytomas (Gasparre et al., 2008), shown that mutations in mtDNA of complex I (ND1) for example, mtDNA mutations in the complex I and III (cytochrome b) led to a considerable decrease of subunits ND2 and ND4–6 were shown to be associated both enzymatic activities and to ROS overproduction in with complex I deficiency and enhanced proliferation thyroid carcinoma (Bonora et al., 2006). In accordance, (Gasparre et al., 2008). By the same token, human cells another study established that the ND6 mutation carrying an overexpressed ND5 mutant were asso- confers a high metastatic potential to its cybrid and ciated with a drop in oxygen consumption, increased was associated with a profound complex I deficiency ROS production, potentiated glucose dependency and and an overproduction of ROS (Ishikawa et al., 2008). enhanced tumour growth (Park et al., 2009). MtDNA Finally, another argument for the relevance of mtDNA mutations of the complex III subunit COXI were found mutations in cancer progression is made by a cybrid in 11 to 12% of all prostate cancer patients screened model with a mutant form of ATP6, the mtDNA-coded in one study and associated with
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