Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1

Yuan Liu,Sarah R Dunn,Mauricio Rojas,Nathaniel M Weathington,Nicholas W Bateman,Erin Steer,Rama K Mallampalli,Travis B Lear,Kent Z.Q Wang,Yu Jiang,P Anthony Otero,Bill B Chen,Manish Verma,Christine Wu,Alison C Mckelvey,Charleen T Chu

doi:10.1172/jci.insight.131834

Abstract

Mitochondrial quality control is mediated by the PTEN-induced kinase 1 (PINK1), a cytoprotective protein that is dysregulated in inflammatory lung injury and neurodegenerative diseases. Here, we show that a ubiquitin E3 ligase receptor component, FBXO7, targets PINK1 for its cellular disposal. FBXO7, by mediating PINK1 ubiquitylation and degradation, was sufficient to induce mitochondrial injury and inflammation in experimental pneumonia. A computational simulation-based screen led to the identification of a small molecule, BC1464, which abrogated FBXO7 and PINK1 association, leading to increased cellular PINK1 concentrations and activities, and limiting mitochondrial damage. BC1464 exerted antiinflammatory activity in human tissue explants and murine lung inflammation models. Furthermore, BC1464 conferred neuroprotection in primary cortical neurons, human neuroblastoma cells, and patient-derived cells in several culture models of Parkinson's disease. The data highlight a unique opportunity to use small molecule antagonists that disrupt PINK1 interaction with the ubiquitin apparatus to enhance mitochondrial quality, limit inflammatory injury, and maintain neuronal viability.

Highlights

PTEN-induced kinase 1 (PINK1), a serine/threonine protein kinase, functions in a critical role for mitochondria quality maintenance [1, 2]
We examined the role of FBXO7 on mitochondrial homeostasis, given the important role played by PINK1 in regulating mitochondrial function
Our discovery that the ubiquitin E3 ligase subunit FBXO7 targets prosurvival, antiinflammatory PINK1 for degradation led us to the development of a mitochondrial protective therapeutic small molecule compound

Summary

Introduction

PTEN-induced kinase 1 (PINK1), a serine/threonine protein kinase, functions in a critical role for mitochondria quality maintenance [1, 2]. Loss-of-function mutations in the PINK1 gene cause mitochondrial dysfunction and an early-onset familial form of Parkinson’s disease [3,4,5]. Mitochondrial protease HtrA2, mitochondrial chaperone TRAP1, Akt, and protein kinase A are known molecular targets described for PINK1 [9,10,11,12,13]. These observations suggest multiple mechanisms whereby PINK1 can regulate mitochondrial and cytosolic substrates that, in turn, impact cellular bioenergetics and human disease

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Conclusion