Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock.

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.

• Authors: Robert S Rogers, Rohit Sharma, Hardik B Shah, Owen S Skinner, Xiaoyan A Guo, Apekshya Panda, Rahul Gupta, Timothy J Durham, Kelsey B Shaughnessy, Jared R Mayers, Kathryn A Hibbert, Rebecca M Baron, B Taylor Thompson, Vamsi K Mootha
• Journal: Metabolomics : Official journal of the Metabolomic Society (Metabolomics) Vol. 20 Issue 2 Pg. 36 (Mar 06 2024) ISSN: 1573-3890 [Electronic] United States
• PMID: 38446263 (Publication Type: Journal Article)
• Copyright: © 2024. The Author(s).

Chemical References

• Amino Acids
• N-Formylmethionine
• Methionine
• Lactic Acid
• Racemethionine

Topics

• Humans
• Amino Acids
• Shock, Septic
• N-Formylmethionine
• Metabolomics
• Sepsis
• Methionine
• Lactic Acid
• Racemethionine
• Mitochondrial Diseases