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Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis.

Abstract：

OBJECTIVE:Mitochondrial damage and dysfunction are thought to play an important role in the pathogenesis of sepsis-induced organ failures. Unfortunately, specific markers of mitochondrial damage in vital organs do not currently exist. Recently, carbomyl phosphate synthase (CPS)-1, a protein primarily localized to liver mitochondria, was found to be present in high concentrations in the plasma of septic humans. Thus, we hypothesized that the circulatory release of CPS-1 would correlate with mitochondrial damage or impaired mitochondrial function in the liver in a clinically relevant model of sepsis. DESIGN:Prospective, randomized, controlled animal study. SETTING:University medical center research laboratory. SUBJECTS:Male, Balb/C mice, aged 10-12 wks. INTERVENTIONS:Animals were assigned to receive cecal ligation and puncture (CLP sepsis) or sham operation and compared with untreated controls. Plasma CPS-1 levels and liver mitochondrial variables, including morphology, respiratory activity, mass (i.e., cardiolipin content), and protein carbonylation, were assessed at various time points (8, 24, and 48 hrs and 6 days) after surgery. MEASUREMENTS AND MAIN RESULTS:Oxidant stress (i.e., carbonylation) was detected within 8 hrs of CLP and persisted through 48 hrs. Plasma CPS-1 levels increased dramatically at 24 hrs, remained significantly elevated at 48 hrs, and normalized by 6 days in the sepsis group. Abnormalities of liver mitochondrial morphology and function coincided with increased plasma CPS-1 levels. Mitochondrial depletion in the liver was not due to cell death but was associated with increased lysosomal clearance. Increased expression of mitochondrial biogenesis factors preceded restoration of mitochondrial variables and normalization of CPS-1 levels by day 6. CONCLUSIONS:Circulating CPS-1 is a marker of mitochondrial damage and depletion in the liver during the subacute phase of CLP sepsis. From a mechanistic standpoint, mitochondrial depletion is not due to cell death but is apparently related to the removal of damaged mitochondria by lysosomes (i.e., autophagy), followed by repletion of mitochondrial populations. Further studies are needed to determine the clinical utility of CPS-1 as a marker of sepsis severity.

journal_name

Crit Care Med

journal_title

Critical care medicine

authors

Crouser ED,Julian MW,Huff JE,Struck J,Cook CH

doi

10.1097/01.CCM.0000230240.02216.21

subject

Has Abstract

pub_date

2006-09-01 00:00:00

pages

2439-46

issue

eissn

0090-3493

issn

1530-0293

journal_volume

pub_type

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Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis.