Plasma mitochondrial DNA and metabolomic alterations in severe critical illness

Abstract Background Cell-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...

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Main Authors: Pär I. Johansson, Kiichi Nakahira, Angela J. Rogers, Michael J. McGeachie, Rebecca M. Baron, Laura E. Fredenburgh, John Harrington, Augustine M. K. Choi, Kenneth B. Christopher
Format: Article
Language:English
Published: BMC 2018-12-01
Series:Critical Care
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13054-018-2275-7
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spelling doaj-d8cb2159232f466d89b93403a74890e62020-11-25T02:36:52ZengBMCCritical Care1364-85352018-12-012211910.1186/s13054-018-2275-7Plasma mitochondrial DNA and metabolomic alterations in severe critical illnessPär I. Johansson0Kiichi Nakahira1Angela J. Rogers2Michael J. McGeachie3Rebecca M. Baron4Laura E. Fredenburgh5John Harrington6Augustine M. K. Choi7Kenneth B. Christopher8Department of Clinical Immunology, Copenhagen University HospitalDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell MedicinePulmonary & Critical Care Medicine, Stanford University Medical CenterChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s HospitalPulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s HospitalPulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s HospitalDivision of Pulmonary and Critical Care Medicine, Department of Medicine, New York Presbyterian-Weill Cornell Medical Center, Weill Cornell MedicineDepartment of Medicine, New York-Presbyterian HospitalRenal Division, Department of Medicine, Brigham and Women’s HospitalAbstract Background Cell-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. Methods We 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. Results Metabolomic 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. Conclusions Differential 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.http://link.springer.com/article/10.1186/s13054-018-2275-7Mitochondrial DNAMetaboliteMetabolomicsHomeostasisCritical illnessAcylcarnitine
collection DOAJ
language English
format Article
sources DOAJ
author Pär I. Johansson
Kiichi Nakahira
Angela J. Rogers
Michael J. McGeachie
Rebecca M. Baron
Laura E. Fredenburgh
John Harrington
Augustine M. K. Choi
Kenneth B. Christopher
spellingShingle Pär I. Johansson
Kiichi Nakahira
Angela J. Rogers
Michael J. McGeachie
Rebecca M. Baron
Laura E. Fredenburgh
John Harrington
Augustine M. K. Choi
Kenneth B. Christopher
Plasma mitochondrial DNA and metabolomic alterations in severe critical illness
Critical Care
Mitochondrial DNA
Metabolite
Metabolomics
Homeostasis
Critical illness
Acylcarnitine
author_facet Pär I. Johansson
Kiichi Nakahira
Angela J. Rogers
Michael J. McGeachie
Rebecca M. Baron
Laura E. Fredenburgh
John Harrington
Augustine M. K. Choi
Kenneth B. Christopher
author_sort Pär I. Johansson
title Plasma mitochondrial DNA and metabolomic alterations in severe critical illness
title_short Plasma mitochondrial DNA and metabolomic alterations in severe critical illness
title_full Plasma mitochondrial DNA and metabolomic alterations in severe critical illness
title_fullStr Plasma mitochondrial DNA and metabolomic alterations in severe critical illness
title_full_unstemmed Plasma mitochondrial DNA and metabolomic alterations in severe critical illness
title_sort plasma mitochondrial dna and metabolomic alterations in severe critical illness
publisher BMC
series Critical Care
issn 1364-8535
publishDate 2018-12-01
description Abstract Background Cell-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. Methods We 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. Results Metabolomic 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. Conclusions Differential 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.
topic Mitochondrial DNA
Metabolite
Metabolomics
Homeostasis
Critical illness
Acylcarnitine
url http://link.springer.com/article/10.1186/s13054-018-2275-7
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