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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish
Article number131834
JournalJCI Insight
Volume5
Issue number11
DOIs
StatePublished - 4 Jun 2020
Externally publishedYes

Fingerprint

Dive into the research topics of 'Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1'. Together they form a unique fingerprint.

Cite this