Insulin signaling regulatesPink1mRNA localization via modulation of AMPK activity to support PINK1 function in neurons

Abstract

AbstractMitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport ofPink1mRNA by tethering it to the mitochondrial surface. Here, we report that inhibition of AMPK by activation of the insulin signaling cascade preventsPink1mRNA binding to mitochondria. Mechanistically, AMPK phosphorylates the RNA anchor complex subunit SYNJ2BP within its PDZ domain, a phosphorylation site that is necessary for its interaction with the RNA-binding protein SYNJ2. Interestingly, loss of mitochondrialPink1mRNA association upon insulin addition is required for PINK1 protein activation and its function as a ubiquitin kinase in the mitophagy pathway, thus placing PINK1 function under metabolic control. Induction of insulin-resistancein vitroby the key genetic Alzheimer-risk factor apolipoprotein E4 retainsPink1mRNA at the mitochondria and prevents proper PINK1 activity especially in neurites. Our results thus identify a metabolic switch controllingPink1mRNA localization and PINK1 activity via insulin and AMPK signaling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.