MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury.
Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis.
Pulmonary, Critical Care and Sleep Medicine, Dept. of Internal Medicine, Yale Univ. School of Medicine, 333 Cedar St., P.O. Box 208057, New Haven, CT 06520-8057. patty.lee@yale.edu.
Praveen
P
Mannam
Amanda S
AS
Shinn
Anup
A
Srivastava
Radu F
RF
Neamu
Wendy E
WE
Walker
Michael
M
Bohanon
Jane
J
Merkel
Min-Jong
MJ
Kang
Charles S
CS
Dela Cruz
Amy M
AM
Ahasic
Margaret A
MA
Pisani
Mark
M
Trentalange
A Phillip
AP
West
Gerald S
GS
Shadel
Jack A
JA
Elias
Patty J
PJ
Lee
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism; D055370:Lung Injury / Q000209:etiology*; D048371:MAP Kinase Kinase 3 / Q000097:blood* / Q000172:deficiency* / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D063306:Mitophagy / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000503:physiopathology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
D008070:Lipopolysaccharides; D048371:MAP Kinase Kinase 3; D011494:Protein Kinases; D056564:Sirtuin 1; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse; C470545:Sirt1 protein, mouse
biogenesis; lung injury; mitochondria; mitogen-activated protein kinases; mitophagy; sepsis