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<p>Mitochondria are semi-autonomous organelles whose functions critically depend on nucleus-encoded proteins. TOM40 is the core β-barrel protein of the translocase of the outer mitochondrial membrane (TOM) complex that mediates the import of most nucleus-encoded mitochondrial proteins. Here, we show that the small GTPase RAB32 facilitates the mitochondrial localization of TOM40 and the mitochondrial protein homeostasis in non-small cell lung cancer (NSCLC) cells. Accordingly, knockout of RAB32 results in mitochondrial dysfunction and inhibits NSCLC progression in xenograft and autochthonous NSCLC mouse models. We further identify ubiquitin-specific peptidase 13 (USP13) that removes the K48-linked polyubiquitin chains from RAB32 to prevent its proteasomal degradation. Consistently, knockout of USP13 causes destabilization of RAB32, impairs TOM40 mitochondrial localization and mitochondrial function, and inhibits NSCLC progression, which are restored by reconstitution of wild-type USP13 or RAB32, but not the catalytically inactive USP13<sup>C345A/M664/739E</sup>. Our study has revealed a previously uncharacterized RAB32-USP13 axis for mitochondrial functions and NSCLC progression.</p><p></p>

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The RAB32-USP13 axis facilitates TOM40 mitochondrial localization to promote non-small cell lung cancer progression

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Hong-Xu Li,
  • Yi-Ting Wei,
  • Hu Gan,
  • Han-Yue Zhang,
  • Xin-Lin Qu,
  • Yijie Zhang,
  • Xiaoping Miao,
  • Bo Zhong,
  • Dandan Lin

摘要

Mitochondria are semi-autonomous organelles whose functions critically depend on nucleus-encoded proteins. TOM40 is the core β-barrel protein of the translocase of the outer mitochondrial membrane (TOM) complex that mediates the import of most nucleus-encoded mitochondrial proteins. Here, we show that the small GTPase RAB32 facilitates the mitochondrial localization of TOM40 and the mitochondrial protein homeostasis in non-small cell lung cancer (NSCLC) cells. Accordingly, knockout of RAB32 results in mitochondrial dysfunction and inhibits NSCLC progression in xenograft and autochthonous NSCLC mouse models. We further identify ubiquitin-specific peptidase 13 (USP13) that removes the K48-linked polyubiquitin chains from RAB32 to prevent its proteasomal degradation. Consistently, knockout of USP13 causes destabilization of RAB32, impairs TOM40 mitochondrial localization and mitochondrial function, and inhibits NSCLC progression, which are restored by reconstitution of wild-type USP13 or RAB32, but not the catalytically inactive USP13C345A/M664/739E. Our study has revealed a previously uncharacterized RAB32-USP13 axis for mitochondrial functions and NSCLC progression.