Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Sepsis-induced brain dysfunction (SIBD) is a critical complication of sepsis.
• Mitochondrial dysfunction is a key factor in SIBD pathogenesis.
• The roles of specific signaling molecules like Src and PTP1B in SIBD are not fully understood.

Purpose of the Study:

• To investigate the involvement of tyrosine kinase Src and protein tyrosine phosphatase 1B (PTP1B) in brain mitochondrial dysfunction during sepsis.
• To elucidate the mechanisms by which Src and PTP1B affect mitochondrial oxidative phosphorylation (OXPHOS) and function.

Main Methods:

• Utilized a lipopolysaccharide (LPS)-induced rat sepsis model.
• Assessed levels of PTP1B and Src in rat brains post-sepsis induction.
• Examined tyrosine phosphorylation of mitochondrial OXPHOS complexes.
• Investigated in vitro effects of PTP1B and Src on mitochondrial complex activities.
• Analyzed interactions between PTP1B, Src, and mitochondrial complexes using co-immunoprecipitation.
• Measured reactive oxygen species production and mitochondrial membrane potential.

Main Results:

• PTP1B levels increased, while Src levels decreased in the rat brain after LPS administration.
• Sepsis induction led to reduced tyrosine phosphorylation of mitochondrial OXPHOS complexes I, II, and III.
• PTP1B inhibited mitochondrial complex I and III activities, whereas Src enhanced activities of complexes I, II, and III.
• Direct interactions were observed between PTP1B/Src and OXPHOS complexes I/III, and between Src and complex II.
• PTP1B promoted reactive oxygen species production and decreased mitochondrial membrane potential, while Src had opposing effects.

Conclusions:

• PTP1B and Src play significant roles in sepsis-induced brain mitochondrial dysfunction.
• Dysregulation of PTP1B and Src leads to decreased mitochondrial protein tyrosine phosphorylation, impacting OXPHOS function.
• These findings highlight PTP1B and Src as potential therapeutic targets for mitigating SIBD.