Structure of human PINK1 at a mitochondrial TOM-VDAC array

  • Science. 2025 Apr 18;388(6744):303-310. doi: 10.1126/science.adu6445.
Sylvie Callegari  1  2 ,  Nicholas S Kirk  1  2 ,  Zhong Yan Gan  1  2 ,  Toby Dite  1  2 ,  Simon A Cobbold  1  2 ,  Andrew Leis  1  2 ,  Laura F Dagley  1  2 ,  Alisa Glukhova  1  2  3  4  5 ,  David Komander  1  2
Affiliations
  • 1. Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
  • 3. Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia.
  • 4. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
  • 5. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
PMID: 40080546 DOI: 10.1126/science.adu6445
Abstract

Mutations in the ubiquitin kinase PINK1 cause early-onset Parkinson's disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-angstrom resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial translocase of the outer membrane (TOM) and voltage-dependent anion channel (VDAC) complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.