Plasma mitochondrial DNA and metabolomic alterations in severe critical illness

Pär I Johansson,Angela J Rogers,Kiichi Nakahira,Augustine M K Choi,John Harrington,Rebecca M Baron,Michael J Mcgeachie,Laura E Fredenburgh,Kenneth B Christopher

doi:10.1186/s13054-018-2275-7

Abstract

BackgroundCell-free plasma mitochondrial DNA (mtDNA) levels are associated with endothelial dysfunction and differential outcomes in critical illness. A substantial alteration in metabolic homeostasis is commonly observed in severe critical illness. We hypothesized that metabolic profiles significantly differ between critically ill patients relative to their level of plasma mtDNA.MethodsWe performed a metabolomic study with biorepository plasma samples collected from 73 adults with systemic inflammatory response syndrome or sepsis at a single academic medical center. Patients were treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to plasma NADH dehydrogenase 1 (ND1) mtDNA levels in critical illness, we first generated metabolomic data using gas and liquid chromatography-mass spectroscopy. We performed fold change analysis and volcano plot visualization based on false discovery rate-adjusted p values to evaluate the distribution of individual metabolite concentrations relative to ND1 mtDNA levels. We followed this by performing orthogonal partial least squares discriminant analysis to identify individual metabolites that discriminated ND1 mtDNA groups. We then interrogated the entire metabolomic profile using pathway overrepresentation analysis to identify groups of metabolite pathways that were different relative to ND1 mtDNA levels.ResultsMetabolomic profiles significantly differed in critically ill patients with ND1 mtDNA levels ≥ 3200 copies/μl plasma relative to those with an ND1 mtDNA level < 3200 copies/μl plasma. Several analytical strategies showed that patients with ND1 mtDNA levels ≥ 3200 copies/μl plasma had significant decreases in glycerophosphocholines and increases in short-chain acylcarnitines.ConclusionsDifferential metabolic profiles during critical illness are associated with cell-free plasma ND1 mtDNA levels that are indicative of cell damage. Elevated plasma ND1 mtDNA levels are associated with decreases in glycerophosphocholines and increases in short-chain acylcarnitines that reflect phospholipid metabolism dysregulation and decreased mitochondrial function, respectively.

Highlights

Cell-free plasma mitochondrial DNA levels are associated with endothelial dysfunction and differential outcomes in critical illness
Patients with NADH dehydrogenase 1 (ND1) mitochondrial DNA (mtDNA) ≥ 3200 copies/μl plasma had a sixfold higher odds of 28-day mortality following adjustment for APACHE Acute Physiology and Chronic Health Evaluation II (II) and sepsis compared with patients with ND1 mtDNA < 3200 copies/μl plasma (OR, 6.4; 95% CI, 1.8–22.9; p = 0.004), similar to what was reported in the parent ND1 mtDNA study [5]
Using high-resolution metabolomics, we demonstrated substantial differences in glycerophospholipid and acylcarnitine family member metabolism based on the level of ND1 mtDNA liberated in the plasma

Summary

Introduction

Cell-free plasma mitochondrial DNA (mtDNA) levels are associated with endothelial dysfunction and differential outcomes in critical illness. Plasma mtDNA is measurable in critically ill patients, with increasing levels associated with sepsis, sepsis disease severity, and mortality [5,6,7]. MtDNA is shown to increase endothelial cell permeability, either directly or through interactions with endothelial cells and polymorphonuclear leukocytes [9]. These findings suggest that plasma mtDNA levels could reflect the level of injury and may reflect the level of dysfunction or damage that mitochondria undergo in response to physiologic stress [10]

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