Abstract for presentation at 11th International Congress of Human Genetics

Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III

  • Dr Elena Bonora, Unit of Medical Genetics-Dept of Internal medicine University of Bologna, Italy
  • Dr Anna Maria Porcelli, Dept of Biology- University of Bologna, Italy
  • Mr Giuseppe Gasparre, Unit of Medical Genetics-Dept of Internal Medicine University of Bologna, Italy
  • Dr Annalisa Biondi, Dept of Biochemistry-University of Bologna, Italy
  • Dr Anna Ghelli, Dept of Biology- University of Bologna, Italy
  • Prof Giorgio Lenaz, Dept of Biochemistry-University of Bologna, Italy
  • Prof Michela Rugolo, Dept of Biology- University of Bologna, Italy
  • Prof Giovanni Romeo, Unit of Medical Genetics-Dept of Internal Medicine University of Bologna, Italy

    • Cells with an aberrant accumulation of mitochondria characterize oncocytic tumors. These tumors commonly arise in the thyroid and their pathogenesis is unknown. In order 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 medium, a condition which forces cells to rely only 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 to 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 a reduced viability and an ATP content similar to that of the parental XTC.UC1, clearly pointing to the existence of mtDNA alterations. Sequencing of XTC.UC1 mtDNA identified two heteroplasmic mutations with a clear pathogenic potential. The first is a frameshift mutation in the ND1 subunit of complex I. The second is a novel missense substitution affecting the catalytic site of cytochrome b in complex III.
    Our work provides the first demonstration that impaired mitochondrial function of XTC.UC1 is due to a combined complex I/III defect associated with mtDNA mutations as proven by the transfer of the biochemical deficiency of the mutant mtDNA into the cybrids. These mutations may represent valuable biomarkers for thyroid oncocytic tumors and contribute to the development of specific treatments for the cure of this potentially lethal form of thyroid cancer.

    Conference Organiser - ICMS Pty Ltd