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<p>During apoptosis, the BCL-2 family members BAX and BAK oligomerize and form a pore to mediate the decisive step of mitochondrial outer membrane permeabilization. However, the contribution of additional cellular components to apoptotic pore dynamics remains poorly understood. Here we map the protein environment of the apoptotic pore using in situ proximity labeling and identify the mitochondrial carrier homolog protein MTCH2 localizing nearby BAX and BAK assemblies specifically under apoptotic conditions. We show that cells lacking MTCH2 exhibit delayed BAX and BAK oligomerization at the single-particle level, which can be rescued by addition of lysophosphatidic acid. Accordingly, MTCH2 depletion decreases not only apoptosis sensitivity but also sublethal mitochondrial permeabilization during bacterial infection, mitochondrial DNA release into the cytosol and cGAS–STING activation under impaired caspases. Our findings uncover a key role of MTCH2 in promoting BAX and BAK high-order assembly with functional consequences for apoptotic pore growth and downstream responses.</p>

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MTCH2 promotes BAX and BAK self-assembly and apoptotic pore growth

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月29日

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  • Hector Flores-Romero,
  • Aida Pena-Blanco,
  • Jonas Aufdermauer,
  • Shashank Dadsena,
  • Philip Neubert,
  • Lisa Hohorst,
  • Eileen Cors,
  • Cristiana Zollo,
  • Alvaro Larrañaga-SanMiguel,
  • Jone Zaldunbide,
  • Maria Nenchova,
  • Yasmin Carvalho-Schaefer,
  • Thomas Langer,
  • Georg Häcker,
  • Ana J. Garcia-Saez

摘要

During apoptosis, the BCL-2 family members BAX and BAK oligomerize and form a pore to mediate the decisive step of mitochondrial outer membrane permeabilization. However, the contribution of additional cellular components to apoptotic pore dynamics remains poorly understood. Here we map the protein environment of the apoptotic pore using in situ proximity labeling and identify the mitochondrial carrier homolog protein MTCH2 localizing nearby BAX and BAK assemblies specifically under apoptotic conditions. We show that cells lacking MTCH2 exhibit delayed BAX and BAK oligomerization at the single-particle level, which can be rescued by addition of lysophosphatidic acid. Accordingly, MTCH2 depletion decreases not only apoptosis sensitivity but also sublethal mitochondrial permeabilization during bacterial infection, mitochondrial DNA release into the cytosol and cGAS–STING activation under impaired caspases. Our findings uncover a key role of MTCH2 in promoting BAX and BAK high-order assembly with functional consequences for apoptotic pore growth and downstream responses.