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. 2024 Mar 6;20(2):36.
doi: 10.1007/s11306-024-02089-z.

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

Robert S Rogers  1   2   3 , Rohit Sharma  4   5 , Hardik B Shah  4   5 , Owen S Skinner  4   5 , Xiaoyan A Guo  5 , Apekshya Panda  5 , Rahul Gupta  4   5 , Timothy J Durham  4   5   6 , Kelsey B Shaughnessy  7 , Jared R Mayers  8 , Kathryn A Hibbert  7 , Rebecca M Baron  8 , B Taylor Thompson  7 , Vamsi K Mootha  9   10   11   12
Affiliations

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

Robert S Rogers et al. Metabolomics. .

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.

Keywords: Kynurenine; Lac-Phe; Lactoyl; Sepsis; Septic shock; f-Met.

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Conflict of interest statement

VKM is a member of the scientific advisory board of 5AM Ventures. RSR began full-time employment with Vertex Pharmaceuticals in September 2023, after the initial submission of this work. Vertex Pharmaceuticals had no role in this study or its publication.

Figures

Fig. 1
Fig. 1
Metabolomics of septic shock in comparison to ambulatory controls, bacteremia without sepsis and cardiogenic shock adjusted for age and sex. Volcano plots of septic shock (n = 42) in comparison to A ambulatory controls (n = 19), B bacteremia without sepsis (n = 18), and C cardiogenic shock (n = 19). Dashed lines denote Padj = 0.05. Venn diagrams quantifying the metabolites significantly (Padj < 0.05) D increased and E decreased in comparison to septic shock with an accompanying list of the metabolites significantly different in septic shock in comparison to all three comparator groups. “f-Met” = N-formyl-l-methionine; “Lac-Phe” = N-Lactoyl-phenylalanine
Fig. 2
Fig. 2
Relationship of f-Met and serine to sepsis severity and mortality. A Relative quantification of f-Met for all subjects. Solid line denotes median. Kruskal–Wallis multiple comparisons test of statistical significance. B Correlation of f-Met and Sequential Organ Failure Assessment (SOFA) score for septic shock subjects. Pearson correlation coefficient. C Relative quantification of f-Met in septic shock 28-day survivors (n = 28) vs. non-survivors (n = 14). Mann–Whitney test of statistical significance. D Absolute quantitation of serine for all subjects. Solid line denotes median. Kruskal–Wallis multiple comparisons test of statistical significance. E Correlation of serine and SOFA score for septic shock subjects. Pearson correlation coefficient. F Absolute quantitation of serine in septic shock 28-day survivors (n = 28) vs. non-survivors (n = 14). Mann–Whitney test of statistical significance. * = P < 0.05, ** = P < 0.01, *** = P < 0.001, **** = P < 0.0001
Fig. 3
Fig. 3
N-Lactoyl-amino acids vs. lactate as distinguishers of sepsis severity and mortality. Absolute quantitation of all subjects (A–E); septic shock subjects divided by SOFA score (n = 12, 15, 15) (F–J); and septic shock 28-day survivors (n = 28) vs. non-survivors (n = 14) (K–O) for the indicated metabolite. For comparisons of illness groups and septic shock SOFA groups, Kruskal–Wallis multiple comparisons test of statistical significance. For comparisons of septic shock mortality, Mann–Whitney test of statistical significance. * = P < 0.05, ** = P < 0.01, *** = P < 0.001, **** = P < 0.0001
Fig. 4
Fig. 4
Interrelationship of lactate, f-Met and Lac-Phe. Correlation of A log (lac-Phe) and log (lactate); B log (f-Met) and log (lactate); and C log (lac-Phe) and log (f-Met) for all subjects color-coded by group
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