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

Abstract

Mitochondrial quality control failure is frequently observed in neurodegenerative diseases. The detection of damaged mitochondria by stabilization of PTEN-induced kinase 1 (PINK1) requires transport of Pink1 mRNA by tethering it to the mitochondrial surface. Here, we report that inhibition of AMPK by activation of the insulin signaling cascade prevents Pink1 mRNA 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 mitochondrial Pink1 mRNA 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-resistance in vitro by the key genetic Alzheimer-risk factor apolipoprotein E4 retains Pink1 mRNA at the mitochondria and prevents proper PINK1 activity especially in neurites. Our results thus identify a metabolic switch controlling Pink1 mRNA localization and PINK1 activity via insulin and AMPK signaling in neurons and propose a mechanistic connection between insulin resistance and mitochondrial dysfunction.

ER-associated biogenesis of PINK1 preprotein for neuronal mitophagy

“…Treatment with the AMPK Activator AICAR had little effect (Fig. 1E-H, consistent with already high AMPK activity in the imaging medium lacking insulin (14). The effect of CC was not due to altered PINK1 processing (Fig.…”

“…Instead, mechanisms anchoring the ribosome and/or mRNAs to the mitochondrion have been described, which rather support cotranslational import (31)(32)(33). However, constant mitochondrial association of Pink1 mRNA prevents PINK1 function in neurons (14), arguing that the mRNA needs to be untethered to produce a fully functional protein. Untethering of Pink1 mRNA might be a prerequisite for mitophagy as it increases the cytosolic dwell time and potentially inhibits co-translational import of the PINK1 precursor.…”

“…S2I-K) or expression of a phospho-mimetic version of SYNJ2BP (S21E, Fig. S2L-M) that prevents the untethering of the Pink1 mRNA (14).…”

The role of mitochondrial RNA association for mitochondrial homeostasis in neurons

“…Also, protein phosphorylation may regulate the localization and translation of mitochondria-associated transcripts. PKA-mediated phosphorylation of AKAP1 increases its binding affinity as mentioned above, and we have recently observed that the master metabolic regulator AMP-activated protein kinase (AMPK) phosphorylates SYNJ2BP [ 129 ]. This phosphorylation is necessary for efficient recruitment of its RNA-binding partner SYNJ2 and thereby regulates the localization of Pink1 mRNA.…”

Role of Mitochondria–ER Contact Sites in Mitophagy

“…Previous studies have shown that, like MFN2 and VDAC1, SYNJ2BP is a Parkin substrate [ 174 , 175 ], suggesting that not only will the MERCS mediated by SYNJ2BP and RRBP1 be released upon Parkin activation, but also the tethering of the Pink1 mRNA could be diminished. Evidence from our lab suggests that release of the Pink1 mRNA from SYNJ2BP and mitochondria stimulates PINK1 production and, thereby, promotes mitophagy [ 180 ].…”