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Structure of human PINK1 at a mitochondrial TOM-VDAC array
Sylvie Callegari1,2, Nicholas S Kirk1,2, Zhong Yan Gan1,2
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Science (New York, N.Y.)
|March 13, 2025
Summary
Mutations in the ubiquitin kinase PINK1 cause Parkinson's disease. This study reveals how PINK1 stabilizes at mitochondrial translocase complexes, explaining its regulation and translocation into mitochondria.
Area of Science:
- Mitochondrial biology
- Neurodegenerative diseases
- Structural biology
Background:
- Mutations in the ubiquitin kinase PINK1 are linked to early-onset Parkinson's disease.
- The mechanism of PINK1 stabilization at mitochondrial translocase complexes is not well understood.
Purpose of the Study:
- To determine the structural basis of PINK1 stabilization at the mitochondrial outer membrane translocase (TOM) complex.
- To elucidate the role of the TOM complex and voltage-dependent anion channel (VDAC) in PINK1 regulation and translocation.
Main Methods:
- Cryo-electron microscopy (cryo-EM) at 3.1 angstrom resolution.
- Structural analysis of endogenous mitochondrial translocase of the outer membrane (TOM) and voltage-dependent anion channel (VDAC) complexes with PINK1.
Main Results:
- A detailed structure of dimeric human PINK1 stabilized at an endogenous TOM-VDAC assembly was determined.
- The structure reveals a symmetric arrangement of TOM core complexes around a VDAC2 dimer, mediated by TOM5 and TOM20, which bind PINK1.
- PINK1 translocation into mitochondria via the TOM40 barrel, guided by TOM7 and TOM22, was elucidated.
Conclusions:
- The study explains PINK1 stabilization at the TOM complex and its regulation by oxidation.
- A novel TOM-VDAC assembly and the mechanism of PINK1 translocation through TOM40 were uncovered.
- This provides insights into the molecular mechanisms underlying Parkinson's disease pathogenesis related to PINK1.
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