Involvement of FANCD2 in Energy Metabolism via ATP5α

Growing evidence supports a general hypothesis that aging and cancer are diseases related to energy metabolism. However, the involvement of Fanconi Anemia (FA) signaling, a unique genetic model system for studying human aging or cancer, in energy metabolism remains elusive. Here, we report that FA complementation group D2 protein (FANCD2) functionally impacts mitochondrial ATP production through its interaction with ATP5α, whereas this relationship was not observed in the mutant FANCD2 (K561R)-carrying cells. Moreover, while ATP5α is present within the mitochondria in wild-type cells, it is instead located mostly outside in cells that carry the non-monoubiquitinated FANCD2. In addition, mitochondrial ATP production is significantly reduced in these cells, compared to those cells carrying wtFANCD2. We identified one region (AA42-72) of ATP5α, contributing to the interaction between ATP5α and FANCD2, which was confirmed by protein docking analysis. Further, we demonstrated that mtATP5α (∆AA42-72) showed an aberrant localization, and resulted in a decreased ATP production, similar to what was observed in non-monoubiquitinated FANCD2-carrying cells. Collectively, our study demonstrates a novel role of FANCD2 in governing cellular ATP production, and advances our understanding of how defective FA signaling contributes to aging and cancer at the energy metabolism level.