Review Mitochondrial gateways to cancer Lorenzo Galluzzi a,b,c,1 , Eugenia Morselli a,b,c,1 , Oliver Kepp a,b,c,1 , Ilio Vitale a,b,c , Alice Rigoni a,b,c , Erika Vacchelli b,c,d , Mickael Michaud a,b,c , Hans Zischka e , Maria Castedo a,b,c , Guido Kroemer a,b,c, * a INSERM, U848, Institut Gustave Roussy, PR1, 39, rue Camille Desmoulins, F-94805 Villejuif, France b Institut Gustave Roussy, F-94805 Villejuif, France c Université Paris-Sud XI, F-94805 Villejuif, France d INSERM, U805, F-94805 Villejuif, France e Institute of Toxicology, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Oberschleissheim, Germany article info Article history: Received 26 May 2009 Received in revised form 12 August 2009 Accepted 13 August 2009 Keywords: Bcl-2 Caspases Mitochondrial transmembrane potential Oncoproteins p53 Tumor suppressors abstract Mitochondria are required for cellular survival, yet can also orchestrate cell death. The peculiar biochemical properties of these organelles, which are intimately linked to their compartmentalized ultrastructure, provide an optimal microenvironment for multiple bio- synthetic and bioenergetic pathways. Most intracellular ATP is generated by mitochondrial respiration, which also represents the most relevant source of intracellular reactive oxygen species. Mitochondria participate in a plethora of anabolic pathways, including cholesterol, cardiolipin, heme and nucleotide biosynthesis. Moreover, mitochondria integrate numer- ous pro-survival and pro-death signals, thereby exerting a decisive control over several biochemical cascades leading to cell death, in particular the intrinsic pathway of apoptosis. Therefore, it is not surprising that cancer cells often manifest the deregulation of one or several mitochondrial functions. The six classical hallmarks of cancer (i.e., limitless replica- tion, self-provision of proliferative stimuli, insensitivity to antiproliferative signals, dis- abled apoptosis, sustained angiogenesis, invasiveness/metastatic potential), as well as other common features of tumors (i.e., avoidance of the immune response, enhanced ana- bolic metabolism, disabled autophagy) may directly or indirectly implicate deregulated mitochondria. In this review, we discuss several mechanisms by which mitochondria can contribute to malignant transformation and tumor progression. Ó 2009 Elsevier Ltd. All rights reserved. 0098-2997/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2009.08.002 Abbreviations: ACL, ATP citrate lyase; AIF, apoptosis inducing factor; AML, acute myeloid leukemia; ANT, adenine nucleotide translocase; BH, Bcl-2 homology domain; CRT, calreticulin; CypD, cyclophilin D; Cyt c, cytochrome c; Dw m , mitochondrial transmembrane potential; DCA, dichloroacetate; ECM, extracellular matrix; EMT, epithelial–mesenchymal transition; EndoG, endonuclease G; ER, endoplasmic reticulum; FASN, fatty acid synthase; FH, fumarate hydratase; HIF-1, hypoxia-inducible factor 1; HK, hexokinase; HSP, heat-shock protein; IjBa, inhibitor of jB a subunit; IjKb,IjB kinase b subunit; IM, mitochondrial inner membrane; IMS, mitochondrial intermembrane space; IP 3 R, inositol 1,4,5-trisphosphate receptor; MAPK, mitogen-activated protein kinase; MEFs, mouse embryonic fibroblasts; MMP, mitochondrial membrane permeabilization; MnSOD, manganese superoxide dismutase; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; mtCK, mitochondrial creatine kinase; OM, mitochondrial outer membrane; PBR, peripheral benzodiazepine receptor; PDGF, platelet-derived growth factor; PDH, pyruvate dehydrogenase; PDK1, PDH kinase 1; PET, positron emission tomography; PFK2, 6-phosphofructo-2-kinase; PI3K, phosphatidylinositol-3 kinase; PINK1, PTEN induced putative kinase 1; PKM2, pyruvate kinase M2 isoform; PTPC, permeability transition pore complex; RNAi, RNA interference; ROS, reactive oxygen species; SDH, succinate dehydrogenase; siRNA, small interfering RNA; Stat, signal transducer and activator of transcription; TCA, tricarboxylic acid; TGF b, transforming growth factor b; TSPO, translocator protein of 18 kDa; VDAC, voltage-dependent anion channel. * Corresponding author. Address: INSERM, U848, Institut Gustave Roussy, PR1, 39, rue Camille Desmoulins, F-94805 Villejuif, France. Tel.: +33 1 4211 6046; fax: +33 1 4211 6047. E-mail address: kroemer@orange.fr (G. Kroemer). 1 These authors equally contributed to the article. Molecular Aspects of Medicine 31 (2010) 1–20 Contents lists available at ScienceDirect Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam