Mutated FANCA Gene Role in the Modulation of Energy Metabolism and Mitochondrial Dynamics in Head and Neck Squamous Cell Carcinoma

Cells. 2022 Jul 30;11(15):2353. doi: 10.3390/cells11152353.

Abstract

Fanconi Anaemia (FA) is a rare recessive genetic disorder characterized by a defective DNA repair mechanism. Although aplastic anaemia is the principal clinical sign in FA, patients develop a head and neck squamous cell carcinoma (HNSCC) with a frequency 500-700 folds higher than the general population, which appears more aggressive, with survival of under two years. Since FA gene mutations are also associated with a defect in the aerobic metabolism and an increased oxidative stress accumulation, this work aims to evaluate the effect of FANCA mutation on the energy metabolism and the relative mitochondrial quality control pathways in an HNSCC cellular model. Energy metabolism and cellular antioxidant capacities were evaluated by oximetric, luminometric, and spectrophotometric assays. The dynamics of the mitochondrial network, the quality of mitophagy and autophagy, and DNA double-strand damage were analysed by Western blot analysis. Data show that the HNSCC cellular model carrying the FANCA gene mutation displays an altered electron transport between respiratory Complexes I and III that does not depend on the OxPhos protein expression. Moreover, FANCA HNSCC cells show an imbalance between fusion and fission processes and alterations in autophagy and mitophagy pathways. Together, all these alterations associated with the FANCA gene mutation cause cellular energy depletion and a metabolic switch to glycolysis, exacerbating the Warburg effect in HNSCC cells and increasing the growth rate. In addition, the altered DNA repair due to the FANCA mutation causes a higher accumulation of DNA damage in the HNSCC cellular model. In conclusion, changes in energy metabolism and mitochondrial dynamics could explain the strict correlation between HNSCC and FA genes, helping to identify new therapeutic targets.

Keywords: Fanconi Anaemia; HNSCC; anaerobic glycolysis; antioxidant defences; autophagy; double-strand DNA damage; mitochondrial fusion and fission; mitophagy; oxidative phosphorylation; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fanconi Anemia Complementation Group A Protein / genetics
  • Fanconi Anemia Complementation Group A Protein / metabolism*
  • Fanconi Anemia* / genetics
  • Fanconi Anemia* / metabolism
  • Fanconi Anemia* / pathology
  • Glycolysis
  • Head and Neck Neoplasms* / genetics
  • Humans
  • Mitochondrial Dynamics
  • Squamous Cell Carcinoma of Head and Neck / genetics

Substances

  • FANCA protein, human
  • Fanconi Anemia Complementation Group A Protein

Grants and funding

This research was funded by Associazione Italiana Ricerca sull’anemia di Fanconi ODV—AIRFA, grant title “Ruolo dell’alterazione citoscheletrica e della disfunzione metabolica associate ai geni fanconi nell’invasività dei tumori testa/collo (HNSSC) nei pazienti affetti da Anemia di Fanconi”, and the APC was funded by AIRFA.