Evaluation of metabolic and molecular alterations in Fanconi Anemia

This thesis investigates the multifaceted metabolic landscape of Fanconi Anemia (FA), a rare genetic disorder characterized by defective DNA repair mechanisms. Through several analyses, it uncovers mitochondrial dysfunction in FA cells, resulting in impaired oxidative phosphorylation and heightened oxidative stress. The altered aerobic metabolism is associated with unbalanced mitochondrial dynamics, characterized by increased fission and decreased fusion. The study also reveals the ineffectiveness of antioxidant defenses in FA cells, which exacerbates cellular damage accumulation and contributes to the onset of aplastic anemia, a leading cause of mortality in FA patients. By targeting diverse metabolic pathways, including but not limited to histone deacetylase inhibition, mitochondrial fission inhibition, and antioxidant interventions, this study identifies potential therapeutic strategies to mitigate mitochondrial dysfunction, reduce oxidative stress, and delay aplastic anemia onset. Moreover, it delves into the inflammatory aspects of FA, revealing associations between oxidative stress, mitochondrial dysfunction, and systemic inflammation. Furthermore, the investigation extends to FA-associated head and neck squamous cell carcinomas, highlighting metabolic similarities with FA cells and suggesting novel therapeutic strategies for the management of this tumor in FA patients. Additionally, the study explores Schwachman-Diamond Syndrome, another rare genetic disease that results in aplastic anemia, revealing mitochondrial abnormalities and oxidative stress management challenges shared with those observed in FA. Through antioxidant interventions, mitochondrial function is restored, confirming the potential of antioxidant therapies in mitigating cellular damage in diseases causing aplastic anemia. Overall, this study underscores the importance of targeting mitochondrial dysfunctions, oxidative stress, inflammation, and mitochondrial dynamics to improve outcomes in FA, SDS, and related conditions, paving the way for personalized therapeutic interventions tailored to the unique genetic and metabolic features of affected patients. In conclusion, this thesis represents a paradigm shift in the study of FA, traditionally centered on DNA repair defects, by elucidating the multifactorial nature of the disease and the significance of metabolic dysfunctions. By unveiling profound mitochondrial abnormalities, inadequate antioxidant responses, and systemic inflammation, this research expands our understanding of FA pathogenesis beyond DNA repair deficiencies. Consequently, it pioneers innovative therapeutic strategies targeting metabolic pathways to mitigate cellular damage and delay disease progression.