Involvement of FANCD2 in Energy Metabolism via ATP5α

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.

Fanconi Anemia Signaling and Cancer

“…Apart from the involvement of FA signaling in the cancer metabolism, the specific FA proteins were recently found to directly participate in the functions of mitochondria [92, 93] wherein many metabolic processes take place [94]. On the other hand, the altered metabolite concentrations or deregulated metabolic flux may work back to promote FA signaling.…”

“…This suggests that FA signaling is important in suppressing tumor development across all stages of tumor progression. In light of the very recent publications reporting the involvement of FA signaling in mitochondria [92, 93] and an overlooked form of FANCD2-V2, which is expressed higher in normal cells compared to the corresponding matched malignant cells [103], it is reasonable to suggest that FA signaling protects human cells substantially from as early as the beginning of neoplastic transformation.…”

Mitoprotective Clinical Strategies in Type 2 Diabetes and Fanconi Anemia Patients: Suggestions for Clinical Management of Mitochondrial Dysfunction

“…After the pioneering report by Mukhopadhyay et al in 2006 [107], it became clear that a FA gene product (FA-G) was associated with MDF, opening the way toward the assumption that FA proteins may be related to the control of mitochondrial activity [108][109][110]. In recent years, a growing body of evidence has been provided assessing that other FA gene products, such as FANCA, FANCC, and FANCD2 are connected to mitochondrial function [111][112][113][114] such as energetic function, altogether providing a link between OS and MDF in FA as well as in a number of cancer-prone genetic diseases, as discussed by Perrone et al [115].…”

A new look at molecular biology of breast cancer

“…With increasing evidence to support a general hypothesis that cancer is one of diseases related closely to cellular metabolism, studies on the involvement of FA signaling in energy metabolism was initiated. As a result, a new role of FANCD2 in governing cellular ATP production was discovered, 38 which was at least attributed to the regulation of ATP5a by FANCD2. This study turned into a new scenario, in which FA proteins perform roles in unstressed cells, distinct from the above, relevant to the cellular responses to genotoxicity.…”