Molecular dissection of the ATAD3B role in mitochondrial function and metabolism.

The maintenance of a proper mitochondrial function is crucial for cellular metabolism, and its dysregulation has been proven to be essential for tumor progression. Recently, a link between ATAD3B expression in cancer cells and their higher malignancy and chemoresistance has been observed. However, the molecular function of this mitochondrial ATPase remains completely unknown. In this study, we have investigated the role of ATAD3B in mitochondrial function in order to understand how its expression could contribute to the development and progression of more aggressive cancer subtypes, such as triple-negative breast cancer (TNBC). We have demonstrated that the expression of ATAD3B is restricted to pluripotent and highly malignant cancer cells, which share common proliferative and metabolic traits. Moreover, we have observed that the overexpression of ATAD3B leads to an alteration of the mitochondrial ultrastructure, a decrease in mitochondrial respiration, and, ultimately, results into a metabolic rewiring towards a more glycolytic phenotype. These findings shed significant new light on the potential role of ATAD3B in regulating tumor cell metabolism, pointing it out as a promising candidate for the development of new therapies against chemoresistant and highly metastatic tumors.