Circulating N-formylmethionine and metabolic shift in critical illness: a multicohort metabolomics study

Abstract

Background Cell stress promotes degradation of mitochondria which release danger-associated molecular patterns that are catabolized to N-formylmethionine. We hypothesized that in critically ill adults, the response to N-formylmethionine is associated with increases in metabolomic shift-related metabolites and increases in 28-day mortality. Methods We performed metabolomics analyses on plasma from the 428-subject Correction of Vitamin D Deficiency in Critically Ill Patients trial (VITdAL-ICU) cohort and the 90-subject Brigham and Women’s Hospital Registry of Critical Illness (RoCI) cohort. In the VITdAL-ICU cohort, we analyzed 983 metabolites at Intensive Care Unit (ICU) admission, day 3, and 7. In the RoCI cohort, we analyzed 411 metabolites at ICU admission. The association between N-formylmethionine and mortality was determined by adjusted logistic regression. The relationship between individual metabolites and N-formylmethionine abundance was assessed with false discovery rate correction via linear regression, linear mixed-effects, and Gaussian graphical models. Results Patients with the top quartile of N-formylmethionine abundance at ICU admission had a significantly higher adjusted odds of 28-day mortality in the VITdAL-ICU (OR, 2.4; 95%CI 1.5–4.0; P = 0.001) and RoCI cohorts (OR, 5.1; 95%CI 1.4–18.7; P = 0.015). Adjusted linear regression shows that with increases in N-formylmethionine abundance at ICU admission, 55 metabolites have significant differences common to both the VITdAL-ICU and RoCI cohorts. With increased N-formylmethionine abundance, both cohorts had elevations in individual short-chain acylcarnitine, branched chain amino acid, kynurenine pathway, and pentose phosphate pathway metabolites. Conclusions The results indicate that circulating N-formylmethionine promotes a metabolic shift with heightened mortality that involves incomplete mitochondrial fatty acid oxidation, increased branched chain amino acid metabolism, and activation of the pentose phosphate pathway. Graphic Abstract

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

“…In sepsis, circulating N -formyl peptides including f-Met contribute to sepsis pathophysiology through damage-associated molecular pattern (DAMP) signaling which amplifies tissue-damaging inflammation (Harrington et al, 2017 ) and inhibits neutrophil defense against secondary nosocomial infection (Kwon et al, 2021 ). As has been described recently in two large ICU cohorts (Sigurdsson et al, 2022 ), we found that f-Met is not only increased in septic shock (Fig. 2 A), but also trended towards being positively correlated with sepsis severity (ρ = 0.29, P = 0.07; Fig.…”

“…Consistent with studies in three large ICU cohorts (Kwon et al, 2021 , Sigurdsson et al, 2022 ) and consistent with studies of ICU molecular epidemiology that circulating levels of mitochondrial constituents (mtDNA (Johansson et al, 2018 , Wang et al, 2020 ) and N -formyl-peptides (Kwon et al, 2021 )) are associated with deleterious ICU outcomes, we found that f-Met is increased in septic shock and positively correlated with both severity and mortality. It has been generally assumed that the increased circulating f-Met in sepsis reflects mitochondrial dysfunction, but because f-Met is also produced by bacteria, its origin is not certain.…”

Shared plasma metabolomic profiles of cognitive and mobility decline predict future dementia

“…The process of methionine entering the ribosome occurs in the mitochondria of eukaryotic cells, Escherichia coli, and other bacteria [31]. Recent data from critically ill patients have shown that circulating N-formylmethionine is related to metabolic shift and high mortality which may involve impaired mitochondrial oxidation, elevated branch chain amino acid metabolism, and triggering the pentose phosphate pathway [32]. Multiple sugars are classified under the label "Hexose" including glucose, galactose, and fructose, which may suggest that high levels of sugar intake or circulating glucose contribute to gait decline.…”

Mitochondrial N-formyl methionine peptides contribute to exaggerated neutrophil activation in patients with COVID-19

“…Of note, levels of fMet were elevated in patients with COVID-19, particularly in critically ill patients. Elevated levels of fMet were recently described in non-COVID-19 critically ill patients, associated with a metabolic shift, and heightened mortality [ 70 ], as well as in patients with other inflammatory conditions, including vasculitis, SSC, and RA, wherein fMet levels contributed to neutrophil activation [ 21 , 30 , 31 ]. However, in COVID-19 patients, levels of fMet only correlated with levels of neutrophil activation markers (calprotectin) in patients with mild-to-moderate disease, whereas for critically ill patients, no such correlations were observed.…”