First Visualization of PINK1 Protein Structure Reveals Critical Parkinson Disease Mechanisms

The first ever visualization of how the PINK1 protein docks to the surface of mitochondria was developed by researchers at the Walter and Elizabeth Hall Institute (WEHI), Melbourne, Australia. The findings, which are published in Science, elucidate key information about the behavior and structure of the PINK1 protein, which is implicated in early-onset Parkinson disease (PD), according to the study authors.

PINK1, a protein directly linked to PD, plays a crucial role in detecting and tagging damaged mitochondria for removal. Mutations in the PINK1 gene are known to cause early-onset PD. Until now, the structure of human PINK1 and its attachment to mitochondria remained unknown.

Using high-resolution cryo-electron microscopy, the researchers at WEHI visualized PINK1 at 3.1-Å resolution, revealing how it stabilizes at mitochondrial translocase complexes. The researchers discovered that PINK1 forms a dimeric structure at an endogenous array of mitochondrial TOM (translocase of the outer membrane) and VDAC (voltage-dependent anion channel) complexes. 

Key findings include how PINK1 enters mitochondria through the TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22 proteins. The arrangement of TOM complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, which also bind to PINK1’s kinase C-lobes.

“This is a significant milestone for Parkinson’s research. It is incredible to finally see PINK1 and understand how it binds to mitochondria,” said David Komander, Laboratory Head of WEHI’s Parkinson’s Disease Research Centre. “Our structure reveals many new ways to change PINK1, essentially switching it on, which will be life-changing for people with Parkinson’s.” 

Source: Callegari S, Kirk NS, Gan ZY, et al. Structure of human PINK1 at a mitochondrial TOM-VDAC array. Science. March 13, 2025. doi: 10.1126/science.adu6445