title: Relevance of mitochondrial genetics and metabolism in cancer development.
abstract: Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron transfer chain or to direct alterations of the mitochondrial respiratory complexes. In some cases, the depression of respiratory activity is clearly the consequence of disruptive mitochondrial DNA (mtDNA) mutations and leads as a consequence to enhanced generation of reactive oxygen species (ROS). By acting both as mutagens and cellular mitogens, ROS may contribute directly to cancer progression. On the basis of our experimental evidence, we suggest a deep implication of the supercomplex organization of the respiratory chain as a missing link between oxidative stress, energy failure, and tumorigenesis. We speculate that under conditions of oxidative stress, a dissociation of mitochondrial supercomplexes occurs, with destabilization of complex I and secondary enhanced generation of ROS, thus leading to a vicious circle amplifying mitochondrial dysfunction. An excellent model to dissect the role of pathogenic, disassembling mtDNA mutations in tumor progression and their contribution to the metabolic reprogramming of cancer cells (glycolysis vs. respiration) is provided by an often underdiagnosed subset of tumors, namely, the oncocytomas, characterized by disruptive mutations of mtDNA, especially of complex I subunits. Such mutations almost completely abolish complex I activity, which slows down the Krebs cycle, favoring a high ratio of α-ketoglutarate/succinate and consequent destabilization of hypoxia inducible factor 1α (HIF1α). On the other hand, if complex I is partially defective, the levels of NAD(+) may be sufficient to implement the Krebs cycle with higher levels of intermediates that stabilize HIF1α, thus favoring tumor malignancy. The threshold model we propose, based on the population-like dynamics of mitochondrial genetics (heteroplasmy vs. homoplasmy), implies that below threshold complex I is present and functioning correctly, thus favoring tumor growth, whereas above threshold, when complex I is not assembled, tumor growth is arrested. We have therefore termed "oncojanus" the mtDNA genes whose disruptive mutations have such a double-edged effect.
authors: Department of Medical and Surgical Sciences, Unit of Medical Genetics, University of Bologna Medical School, 40138 Bologna, Italy.
authors: Giuseppe
authors: G
authors: Gasparre
authors: Anna Maria
authors: AM
authors: Porcelli
authors: Giorgio
authors: G
authors: Lenaz
authors: Giovanni
authors: G
authors: Romeo
mesh_terms: D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000737:chemistry; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species
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