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

PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in C. elegans. These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.Abbreviations: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.