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<p>The aberrant Wnt/β-catenin signaling is tightly associated with developmental disorders and tumorigenesis. However, spatial regulation of cytoplasmic β-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 β-catenin localization and its activation. Transcriptome profiling across multiple cancer patient datasets revealed that AK3 and oxidative phosphorylation pathway are highly correlated with Wnt/β-catenin signaling and prognosis of patients. Using cancer cell lines, we found that AK3 enzymatic activity inhibited β-catenin signaling and cell proliferation by attenuating nuclear β-catenin accumulation. Intriguingly, mitofusins (MFN1 &amp; 2) were identified as β-catenin interactors and demanded for the AK3-mediated β-catenin signaling regulation. Additionally, β-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 β-catenin signaling through modulating the β-catenin-mitofusins interactions.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Muhah Jeong,
  • Shin-Hyeon Ryu,
  • Young-Sin Cho,
  • Do-Hyeong Na,
  • Jongyeon Baek,
  • Jihoon Nah,
  • Ki Woo Kim,
  • Yong-Keun Jung

摘要

The aberrant Wnt/β-catenin signaling is tightly associated with developmental disorders and tumorigenesis. However, spatial regulation of cytoplasmic β-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 β-catenin localization and its activation. Transcriptome profiling across multiple cancer patient datasets revealed that AK3 and oxidative phosphorylation pathway are highly correlated with Wnt/β-catenin signaling and prognosis of patients. Using cancer cell lines, we found that AK3 enzymatic activity inhibited β-catenin signaling and cell proliferation by attenuating nuclear β-catenin accumulation. Intriguingly, mitofusins (MFN1 & 2) were identified as β-catenin interactors and demanded for the AK3-mediated β-catenin signaling regulation. Additionally, β-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 β-catenin signaling through modulating the β-catenin-mitofusins interactions.