STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• PTEN induced kinase 1 (PINK1) and Parkin (PRKN) are central to PINK1-PRKN-mediated mitophagy, a process critical for clearing damaged mitochondria.
• While PINK1 cleavage and degradation are understood under basal conditions, the regulation of full-length PINK1 stability after mitochondrial damage remains unclear.

Purpose of the Study:

• To identify mechanisms regulating full-length PINK1 stability during mitophagy.
• To investigate the role of the STUB1-VCP/p97 axis in PINK1 regulation and its implications in Alzheimer disease (AD).

Main Methods:

• Utilized biochemical assays to characterize the interaction and ubiquitination of PINK1.
• Employed proteasomal degradation assays and mitophagy assessments.
• Analyzed patient-derived samples and utilized *C. elegans* models to study disease relevance.

Main Results:

• Identified STUB1 as an E3 ubiquitin ligase that targets full-length PINK1 for K48-linked polyubiquitination.
• Demonstrated that Valosin-containing protein (VCP)/p97 extracts ubiquitinated PINK1 for proteasomal degradation.
• Showed that disruption of the STUB1-VCP/p97 axis leads to excessive PINK1 accumulation, PRKN turnover, and impaired mitophagy.
• Found this regulatory mechanism compromised in Alzheimer disease (AD) brains, leading to neuronal mitophagy defects and impaired learning in *C. elegans*.

Conclusions:

• The STUB1-VCP/p97 complex is a key regulator of full-length PINK1 levels, ensuring efficient mitophagy and mitochondrial homeostasis.
• Dysregulation of this axis contributes to neurodegeneration observed in Alzheimer disease (AD).
• This pathway represents a potential therapeutic target for mitochondrial dysfunction in neurodegenerative diseases.