Year: 2026
Type: preprint
Abstract: Under mitochondrial stress, the mitochondrial kinase PINK1 is activated to phosphorylate ubiquitin, which in turn recruits the E3 ligase Parkin, thereby initiating clearance of damaged mitochondria. Dysregulation of the PINK1–Parkin signaling pathway is associated with early- onset autosomal recessive Parkinson’s disease. However, the mechanisms governing PINK1 conformational dynamics and activation in response to mitochondrial stress remain poorly understood. Here, we report that Tribolium castaneum PINK1 ( Tc PINK1) forms specific symmetric dimers via interactions between the kinase N-lobe and the regulatory C-terminal domain. These dimers undergo dynamic conformational transitions across distinct states, including an autoinhibited state, an inactive intermediate state, a primed-activation state and an active state. Moreover, Tc PINK1 undergoes lateral trans-phosphorylation through dimer–dimer interactions. Notably, symmetric dimer formation is essential for Parkin recruitment during mitophagy. These findings provide a framework for understanding the conformational plasticity and allosteric regulation of PINK1 in mitophagy.
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204144189