title: Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma.
abstract: Mutations in mitochondrial DNA (mtDNA) are frequent in cancers but it is not yet clearly established whether they are modifier events involved in cancer progression or whether they are a consequence of tumorigenesis. Here we show a benign tumor type in which mtDNA mutations that lead to complex I (CI) enzyme deficiency are found in all tumors and are the only genetic alteration detected. Actually renal oncocytomas are homogeneous tumors characterized by dense accumulation of mitochondria and we had found that they are deficient in electron transport chain complex I (CI, NADH-ubiquinone oxidoreductase). In this work total sequencing of mtDNA showed that 9/9 tumors harbored point mutations in mtDNA, seven in CI genes, one in complex III, and one in the control region. 7/8 mutations were somatic. All tumors were somatically deficient for CI. The clonal amplification of mutated mtDNA in 8/9 tumors demonstrates that these alterations are selected and therefore favor or trigger growth. No nuclear DNA rearrangement was detected beside mtDNA defects. We hypothesize that functional deficiency of the oxidative phosphorylation CI could create a loop of amplification of mitochondria during cell division, impair substrates oxidation and increase intermediary metabolites availability.
authors.affiliation: Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.forename: Eric
authors.initials: E
authors.lastname: Hervouet
authors.forename: Elodie
authors.initials: E
authors.lastname: de Laplanche
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Demont
authors.forename: Lucia Fiammetta
authors.initials: LF
authors.lastname: Pennisi
authors.forename: Marc
authors.initials: M
authors.lastname: Colombel
authors.forename: Florence
authors.initials: F
authors.lastname: Mège-Lechevallier
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.forename: Roel
authors.initials: R
authors.lastname: Smeets
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: James
authors.initials: J
authors.lastname: Lespinasse
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.forename: Catherine
authors.initials: C
authors.lastname: Godinot
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.forename: Hélène
authors.initials: H
authors.lastname: Simonnet
mesh_terms: D018249:Adenoma, Oxyphilic / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000235:genetics; D049109:Cell Proliferation; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D009245:NADH Dehydrogenase; D002950:Citrate (si)-Synthase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D042967:Electron Transport Complex I; D005947:Glucose