title: Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III.
abstract: Oncocytic tumors are characterized by cells with an aberrant accumulation of mitochondria. To assess mitochondrial function in neoplastic oncocytic cells, we studied the thyroid oncocytic cell line XTC.UC1 and compared it with other thyroid non-oncocytic cell lines. Only XTC.UC1 cells were unable to survive in galactose, a condition forcing cells to rely solely on mitochondria for energy production. The rate of respiration and mitochondrial ATP synthesis driven by complex I substrates was severely reduced in XTC.UC1 cells. Furthermore, the enzymatic activity of complexes I and III was dramatically decreased in these cells compared with controls, in conjunction with a strongly enhanced production of reactive oxygen species. Osteosarcoma-derived transmitochondrial cell hybrids (cybrids) carrying XTC.UC1 mitochondrial DNA (mtDNA) were generated to discriminate whether the energetic failure depended on mitochondrial or nuclear DNA mutations. In galactose medium, XTC.UC1 cybrid clones showed reduced viability and ATP content, similarly to the parental XTC.UC1, clearly pointing to the existence of mtDNA alterations. Sequencing of XTC.UC1 mtDNA identified a frameshift mutation in ND1 and a nonconservative substitution in cytochrome b, two mutations with a clear pathogenic potential. In conclusion, this is the first demonstration that mitochondrial dysfunction of XTC.UC1 is due to a combined complex I/III defect associated with mtDNA mutations, as proven by the transfer of the defective energetic phenotype with the mitochondrial genome into the cybrids.
authors.affiliation: Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Italy. elena.bonora@eurogene.org
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Porcelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.forename: Annalisa
authors.initials: A
authors.lastname: Biondi
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baracca
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lenaz
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
mesh_terms: D018249:Adenoma, Oxyphilic / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D014450:Electron Transport Complex III / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III