Mitochondria and Cancer
Mitochondria contained in cancer cells exhibit two major alterations. First, they are often relatively resistant to the induction of mitochondrial membrane permeabilization (MMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. The mechanisms of MMP resistance have come under close scrutiny because apoptosis resistance constitutes one of the essential hallmarks of cancer. Second, cancer cell mitochondria often exhibit a reduced oxidative phosphorylation, meaning that ATP is generated through the conversion of glucose to pyruvate and excess pyruvate is then eliminated as the waste product lactate. This glycolytic mode of energy production is even observed in conditions of high oxygen tension and is hence called anaerobic glycolysis. Here, we discuss the molecular mechanisms accounting for inhibition of the mitochondrial apoptosis pathway in neoplasia and discuss possible mechanistic links between MMP resistance and anaerobic glycolysis.
KeywordsOuter Mitochondrial Membrane Anaerobic Glycolysis Mitochondrial Membrane Permeabilization Permeability Transition Pore Complex SDHD Gene
G. Kroemer is supported by Ligue Nationale Contre le Cancer (équipe labellisée), the European Union (Active p53, ChemoRes, DeathTrain, TransDeath, RIGHT), Cancéropôle Ile-de-France, Institut National du Cancer, and the Agence Nationale pour la Recherche. P. Rustin is supported by Association Contre les Maladies Mitochondriales et Association Française Contre les Myopathies, Leducq Foundation (CarDiaNet), and the European Union (Eumitocombat).
- Briere JJ, Favier J, Benit P, El Ghouzzi V, Lorenzato A, Rabier D, Di Renzo MF, Gimenez-Roqueplo AP, Rustin P (2005a) Mitochondrial succinate is instrumental for HIF1alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Hum Mol Genet 14:3263–3269CrossRefPubMedGoogle Scholar
- Favier J, Briere JJ, Strompf L, Amar L, Filali M, Jeunemaitre X, Rustin P, Gimenez-Roqueplo AP (2005) Hereditary paraganglioma/pheochromocytoma and inherited succinate dehydrogenase deficiency. Horm Res 63:171–179Google Scholar
- Geromel V, Kadhom N, Cebalos-Picot I, Ouari O, Polidori A, Munnich A, Rotig A, Rustin P (2001) Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA. Hum Mol Genet 10:1221–1228CrossRefPubMedGoogle Scholar
- Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X (2001) The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 69:1186–1197CrossRefPubMedGoogle Scholar
- Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandenabeele P, Zhivotovsky B, Blagosklonny MV, Malorni W, Knight RA et al (2005) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 12 [Suppl 2]:1463–1467Google Scholar
- Pedersen PL (2007) Warburg, me and hexokinase 2: multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 39:211–222Google Scholar
- Senoo-Matsuda N, Yasuda K, Tsuda M, Ohkubo T, Yoshimura S, Nakazawa H, Hartman PS, Ishii N (2001) A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans. J Biol Chem 276:41553–41558CrossRefPubMedGoogle Scholar
- Warburg O, Poesener K, Negelein E (1924) Über den Stoffwechsel der Tumoren [On metabolism of tumors]. Biochem Z 152:319–344Google Scholar
- Welsh SJ, Bellamy WT, Briehl MM, Powis G (2002) The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 62:5089–5095PubMedGoogle Scholar