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<p>Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner&#xa0;membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner&#xa0;membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1’s transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1’s α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and&#xa0;retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson’s disease.</p>

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Transmembrane domain switching controls PINK1 import and fate in mitochondria

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • James S Lorriman,
  • Rhiannon J Hughes,
  • Adam G Grieve,
  • Robin A Corey,
  • Ian Collinson

摘要

Mitochondrial targeting of the PINK1 kinase results, under normal conditions, in membrane-potential-driven inner membrane penetration and cleavage by the resident protease PARL before retro-translocation and proteasomal degradation. In compromised mitochondria, with reduced membrane potential, inner membrane incorporation is not achieved, which leads to surface activation of the full-length protein, Parkin recruitment and mitophagy. Here, we identify a third pathway in which PINK1 is imported into the mitochondrial matrix. Structural modelling predicts that PINK1’s transmembrane domain (TMD) is conformationally plastic, forming either an α-helix or α/β-hybrid at the interface between Tim17 of the TIM23-complex for engagement of either ROMO1 or PARL. These mutually exclusive assemblies define distinct protein-import channels with differing biological roles. PINK1’s α-helical TMD adopts a pose suggestive of translocation through the ROMO1/Tim17-channel, while the α/β-hybrid engages PARL and is cleaved. We propose that TMD structural plasticity determines whether PINK1 is imported into the matrix or cleaved and retro-translocated. The results expand the role of PINK1 beyond that of a damage sensor and imply a role in healthy mitochondrial function with potential relevance to Parkinson’s disease.