Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury.
High levels of inspired oxygen, hyperoxia, are frequently used in patients with acute respiratory failure. Hyperoxia can exacerbate acute respiratory failure, which has high mortality and no specific therapies. We identified novel roles for PTEN-induced putative kinase 1 (PINK1), a mitochondrial protein, and the cytosolic innate immune protein NLRP3 in the lung and endothelium. We generated double knockouts (PINK1(-/-)/NLRP3(-/-)), as well as cell-targeted PINK1 silencing and lung-targeted overexpression constructs, to specifically show that PINK1 mediates cytoprotection in wild-type and NLRP3(-/-) mice. The ability to resist hyperoxia is proportional to PINK1 expression. PINK1(-/-) mice were the most susceptible; wild-type mice, which induced PINK1 after hyperoxia, had intermediate susceptibility; and NLRP3(-/-) mice, which had high basal and hyperoxia-induced PINK1, were the least susceptible. Genetic deletion of PINK1 or PINK1 silencing in the lung endothelium increased susceptibility to hyperoxia via alterations in autophagy/mitophagy, proteasome activation, apoptosis, and oxidant generation.
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520.
Yi
Y
Zhang
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520.
Maor
M
Sauler
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520.
Amanda S
AS
Shinn
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520.
Huan
H
Gong
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520.
Maria
M
Haslip
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520.
Peiying
P
Shan
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520.
Praveen
P
Mannam
Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT 06520 patty.lee@yale.edu.
Patty J
PJ
Lee
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D004727:Endothelium / Q000276:immunology* / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018496:Hyperoxia / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016877:Oxidants / Q000009:adverse effects*; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology*; D000099202:PTEN-Induced Putative Kinase
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016877:Oxidants; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C492716:Nlrp3 protein, mouse