When more PINK1 is not better

PTEN-induced kinase 1 (PINK1) is well known as a mitochondrial fitness sensor that initiates mitophagy.Our recent study shows that PINK1 signaling also needs timely restraint, linking mitophagy fine-tuning to neuronal function and Alzheimer's disease (AD) [1, 2].Neurons are among the longest-lived cells in the body.Over decades, they must maintain a functional mitochondrial network to sustain synaptic transmission, axonal transport, and local energy demand.This long-term dependence on mitochondrial integrity places mitochondrial quality control at the center of brain aging and neurodegenerative disease.In AD, impaired mitophagy has been observed in postmortem brain samples and disease models, whereas genetic or pharmacological enhancement of mitophagy reduces amyloidβ and tau pathologies and improves cognitive phenotypes in AD model systems [3,4].Evidence from multiple AD models further points to a protective role for PINK1.Restoration of PINK1 signaling attenuates amyloid pathology and mitochondrial dysfunction, whereas loss of PINK1 exacerbates mitochondrial and synaptic defects [5].Together, these studies support a protective role for PINK1-dependent mitophagy in maintaining neuronal mitochondrial homeostasis and limiting AD-related pathology.However, the view that increasing PINK1 is invariably beneficial needs to be reconsidered.PINK1-dependent mitophagy is built on a tightly controlled damage-sensing mechanism [6].In healthy mitochondria, PINK1 is imported, cleaved by mitochondrial proteases, and rapidly degraded by the proteasome.Upon mitochondrial depolarization, fulllength PINK1 accumulates on the outer mitochondrial membrane, phosphorylates ubiquitin and parkin RBR E3 ubiquitin protein ligase (PRKN), and initiates a feed-forward ubiquitin signal that recruits mitophagy receptors such as optineurin (OPTN) and calcium binding and coiled-coil domain 2 (CALCOCO2/NDP52).These receptors then bridge damaged mitochondria to the autophagy machinery, promoting autophagic engulfment and subsequent lysosomal degradation.While this activation step is essential for mitochondrial clearance, how cells regulate full-length PINK1