Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock
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Published:2024-03-06
Issue:2
Volume:20
Page:
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ISSN:1573-3890
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Container-title:Metabolomics
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language:en
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Short-container-title:Metabolomics
Author:
Rogers Robert S.,Sharma Rohit,Shah Hardik B.,Skinner Owen S.,Guo Xiaoyan A.,Panda Apekshya,Gupta Rahul,Durham Timothy J.,Shaughnessy Kelsey B.,Mayers Jared R.,Hibbert Kathryn A.,Baron Rebecca M.,Thompson B. Taylor,Mootha Vamsi K.
Abstract
Abstract
Introduction
Sepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging.
Objective
To assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality.
Methods
We performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) – the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact.
Results
Nine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-l-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased.
Conclusion
Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.
Funder
Parker B. Francis Family Foundation MGH Molecular Biology -- Mootha Lab Sundry Fund J. Willard and Alice S. Marriott Foundation
Publisher
Springer Science and Business Media LLC
Reference60 articles.
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