Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels.
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.
['Lyu|Juanjuan|J|', 'Zheng|Guilang|G|', 'Chen|Zhijiang|Z|', 'Wang|Bin|B|', 'Tao|Shaohua|S|', 'Xiang|Dan|D|', 'Xie|Meiyan|M|', 'Huang|Jinda|J|', 'Liu|Cui|C|', 'Zeng|Qiyi|Q|']
D000818:Animals D001921:Brain D004195:Disease Models, Animal D008070:Lipopolysaccharides D008297:Male D053078:Membrane Potential, Mitochondrial D008928:Mitochondria D010766:Phosphorylation D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 D012333:RNA, Messenger D017208:Rats, Wistar D017382:Reactive Oxygen Species D018805:Sepsis D065166:Sepsis-Associated Encephalopathy D019061:src-Family Kinases
Mitochondrial dysfunction Src PTP1B Sepsis-induced brain dysfunction Tyrosine phosphorylation