title: Attenuation of mitochondrial unfolded protein response is associated with hepatic dysfunction in septic rats.
abstract: This study was conducted to reveal if the mitochondrial unfolded protein response (mtUPR), a conserved mitochondrial-nuclear communication mechanism, plays a critical role in the protein quality control system to cope with damaged protein during sepsis. Sepsis was induced by cecal ligation and puncture (CLP) in Sprague-Dawley rats. The efficiency of mtUPR was evaluated by measuring the transcriptional factors (CCAAT/enhancer-binder protein homologous protein [CHOP] and CCAAT/enhancer-binder protein-β) and chaperones (heat shock protein 60 [Hsp60] and Hsp10) expression in response to hepatic mitochondrial oxidized proteins (carbonylated proteins, car-proteins) and multi-ubiquitinated proteins (ub-proteins). The results showed that car-proteins and ub-proteins were significantly increased at 9 and 18 h after CLP. In addition, serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase were significantly positively correlated with mitochondrial car-proteins and ub-proteins and negatively with intramitochondrial adenosine triphosphate. The expression of mitochondrial Hsp60 and Hsp10 decreased notably during the progression of sepsis, implying that failure of mtUPR occurred in the late septic liver. Interestingly, we evaluated the ratio of mitochondrial Hsp60/Hsp10 to the ub-proteins and found that both ratios were statistically lowered at the time points of 9 and 18 h in comparison with 3 and 6 h after CLP. These ratios were also significantly negatively correlated with glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase levels, suggesting that the ratios could act as an index of mtUPR failure and be a useful tool in estimating the ability of mitochondrial-nuclear communication in sepsis. In conclusion, the results indicated that mtUPR failure occurred during sepsis, and that the index of mtUPR may be a valuable measurement in assessing the severity of organ dysfunction in the clinical setting.
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Taiwan.
authors.forename: Li-Ju
authors.initials: LJ
authors.lastname: Huang
authors.forename: Huei-Ping
authors.initials: HP
authors.lastname: Dong
authors.forename: I-Chun
authors.initials: IC
authors.lastname: Chuang
authors.forename: Maw-Shung
authors.initials: MS
authors.lastname: Liu
authors.forename: Rei-Cheng
authors.initials: RC
authors.lastname: Yang
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D018835:Chaperonin 10 / Q000378:metabolism; D018834:Chaperonin 60 / Q000378:metabolism; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D050050:Protein Carbonylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D018835:Chaperonin 10; D018834:Chaperonin 60; C497251:Ddit3 protein, rat; D024101:Mitochondrial Proteins; D057149:Ubiquitinated Proteins; D051742:Transcription Factor CHOP