TY - JOUR
T1 - Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1
AU - Liu, Yuan
AU - Lear, Travis B.
AU - Verma, Manish
AU - Wang, Kent Z.Q.
AU - Otero, P. Anthony
AU - McKelvey, Alison C.
AU - Dunn, Sarah R.
AU - Steer, Erin
AU - Bateman, Nicholas W.
AU - Wu, Christine
AU - Jiang, Yu
AU - Weathington, Nathaniel M.
AU - Rojas, Mauricio
AU - Chu, Charleen T.
AU - Chen, Bill B.
AU - Mallampalli, Rama K.
N1 - Funding Information:
We thank Shristi Rajbhandari, Olivia Iannone, Jason Callio, and Jacob Jerome for technical assistance. This work was supported, in part, by American Heart Association Scientist Development Grant 16SDG27650008 (YL). This work was supported, in part, by NIH grants HL096376, HL097376, HL098174, HL081784, and P01 HL114453 (RKM); AG026389, NS101628 (cofunded by NINDS/NIA), and NS065789 (CTC); HL139860 and HL133184 (BBC); and HL142777 (YL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported, in part, by the United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, a Merit Review Award from the United States Department of Veterans Affairs (RKM), and the Helen Mendel Fund (CTC).
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/6/4
Y1 - 2020/6/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85086061136&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.131834
DO - 10.1172/jci.insight.131834
M3 - Article
C2 - 32493843
AN - SCOPUS:85086061136
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 11
M1 - 131834
ER -