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bioRxiv · 10.1101/2024.11.06.622366

Alternative Import-Channels And Destinations Of Mitochondrial PINK1 Controlled By Trans-Membrane-Domain Structural Plasticity

Lorriman, J.·Grieve, A.·Corey, R.·Collinson, I.
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Abstract

Entry of the PINK1-kinase into the mitochondrial inner-membrane results in cleavage by the rhomboid-protease PARL, followed by retro-translocation back to the outer-membrane and proteasomal-degradation. Failure of this process, in compromised mitochondria, leads to kinase activation at the surface, and ultimately mitophagy. Analysis of PINK1-import within intact cells reveals an alternative pathway into the matrix. Structural modelling predicts that PINK1s trans-membrane-domain (TMD) forms either an -helix or /{beta}-hybrid at the interface between Tim17, of the TIM23-core-complex, and, respectively, either Romo1 or PARL. These mutually exclusive interactions both encapsulate a hydrated protein-channel. The -helical-TMD form adopts a pose suggestive of translocation through the Romo1/Tim17-channel, while the /{beta}-hybrid-TMD is retracted into PARLs active-site for cleavage, presumably after import through the adjacent rhomboid/Tim17-channel. We propose structural plasticity of the PINK1-TMD underlies alternative destinies for full-length matrix-import or cleavage/retro-translocation. The results reveal new insights of PINK1s role in mitochondrial function, quality-control and early-onset Parkinsons disease.

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Lorriman, J., Grieve, A., Corey, R., Collinson, I.. 2024-11-06. Alternative Import-Channels And Destinations Of Mitochondrial PINK1 Controlled By Trans-Membrane-Domain Structural Plasticity. https://doi.org/10.1101/2024.11.06.622366

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