title: Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels.
abstract: Sepsis-induced brain dysfunction (SIBD) is often the first manifestation of sepsis, and its pathogenesis is associated with mitochondrial dysfunction. In this study, we investigated the roles of the tyrosine kinase Src and protein tyrosine phosphatase 1B (PTP1B) in brain mitochondrial dysfunction using a rat model of lipopolysaccharide (LPS)-induced sepsis. We found that there was a gradual and significant increase of PTP1B levels in the rat brain after sepsis induction. In contrast, brain Src levels were reduced in parallel with the PTP1B increase. Sepsis led to significantly reduced tyrosine phosphorylation of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, II and III. Pretreatment of mitochondrial proteins with active PTP1B significantly inhibited complexes I and III activities in vitro, whereas Src enhanced complexes I, II, and III activities. PTP1B and Src were each co-immunoprecipitated with OXPHOS complexes I and III, suggesting direct interactions between both proteins and complexes I and III. Src also directly interacted with complex II. Furthermore, pretreatment of mitochondrial proteins with active PTP1B resulted in overproduction of reactive oxygen species and decreased mitochondrial membrane potential. Pretreatment with active Src produced the opposite effect. These results suggest that brain mitochondrial dysfunction following LPS-induced sepsis in rats is partly attributed to PTP1B and Src mediated decrease in mitochondrial protein tyrosine phosphorylation.
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Lyu
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Guilang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Zhijiang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Tao
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xiang
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Jinda
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China. Electronic address: zengqy_zj@163.com.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D008070:Lipopolysaccharides; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000503:physiopathology*; D065166:Sepsis-Associated Encephalopathy / Q000209:etiology / Q000503:physiopathology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516610:Ptpn1 protein, rat
keywords: Mitochondrial dysfunction; PTP1B; Sepsis-induced brain dysfunction; Src; Tyrosine phosphorylation