Abstract
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.
Highlights
At the beginning of the twentieth century, Otto Warburg demonstrated the unique metabolic capabilities that cancer cells possess, preferentially utilizing glycolysis for energetic and anabolic purposes, whilst producing a large amount of lactic acid[1]
Our results indicate that cells deficient in the activation of FANCD2 may have an improper function of ATP5α, thereby influencing mitochondrial function
FANCD2 is the only protein highly conserved across all species, compared to many other members in the Fanconi Anemia (FA) pathway, whose homologs are only present in mammals/vertebrates[42]
Summary
At the beginning of the twentieth century, Otto Warburg demonstrated the unique metabolic capabilities that cancer cells possess, preferentially utilizing glycolysis for energetic and anabolic purposes, whilst producing a large amount of lactic acid[1] He defined this “aerobic glycolysis” and hypothesized that disturbances in mitochondrial activity played a specific, pathogenic role in cancer development[2]. We report that FANCD2 contributes to the maintenance of mitochondrial function by partnering with ATP5α, a subunit of ATP synthase, located at the inner membrane of mitochondria[32] These results demonstrate a previously unknown role of FANCD2 in governing cellular ATP production, advancing our understanding of how defective FA signaling contributes to aging and cancer through the scope of energy metabolism
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