Mitochondrial AK3 inhibits nuclear β-catenin localization and its activation through enhancing mitochondrial activity

Abstract

The aberrant Wnt/beta-catenin signaling is tightly associated with developmental disorders and tumorigenesis. However, spatial regulation of cytoplasmic beta-catenin with regard to its nuclear accumulation and signaling activation remains poorly understood. Herein, we show that mitochondrial adenylate kinase 3 (AK3), which is involved in the TCA cycle, regulates nuclear beta-catenin localization and its activation. Transcriptome profiling across multiple cancer patient datasets revealed that AK3 and oxidative phosphorylation pathway are highly correlated with Wnt/beta-catenin signaling and prognosis of patients. Using cancer cell lines, we found that AK3 enzymatic activity inhibited beta-catenin signaling and cell proliferation by attenuating nuclear beta-catenin accumulation. Intriguingly, mitofusins (MFN1 & 2) were identified as beta-catenin interactors and demanded for the AK3-mediated beta-catenin signaling regulation. Additionally, beta-catenin-mitofusins interactions were enhanced by AK3 expression but disrupted by treatment with CCCP. These results suggest that metabolically active mitochondria induced by AK3 restrain beta-catenin signaling through modulating the beta-catenin-mitofusins interactions.