Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock

Scott L. Weiss, Natalie Z. Cvijanovich, Geoffrey L. Allen, Neal J. Thomas, Robert J. Freishtat, Nick Anas, Keith Meyer, Paul A. Checchia, Thomas P. Shanley, Michael T. Bigham, Julie Fitzgerald, Sharon Banschbach, Eileen Beckman, Kelli Howard, Erin Frank, Kelli Harmon, Hector R. Wong*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Introduction: Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis. Methods: We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock. Results: In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C. Conclusions: Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.

Original languageEnglish (US)
Article number623
JournalCritical Care
Volume18
Issue number6
DOIs
StatePublished - Nov 19 2014

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Septic Shock
Transcriptome
Mitochondrial Genes
Pediatrics
Electron Transport Complex I
Sepsis
Down-Regulation
Genes
Energy Metabolism
Blood Cells
Genome
Databases
Peroxisome Proliferator-Activated Receptors
Gene Regulatory Networks
Ribosomal Proteins
Mitochondrial Proteins
Oxidative Phosphorylation
Electron Transport
Computational Biology
RNA

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Weiss, S. L., Cvijanovich, N. Z., Allen, G. L., Thomas, N. J., Freishtat, R. J., Anas, N., ... Wong, H. R. (2014). Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock. Critical Care, 18(6), [623]. https://doi.org/10.1186/s13054-014-0623-9
Weiss, Scott L. ; Cvijanovich, Natalie Z. ; Allen, Geoffrey L. ; Thomas, Neal J. ; Freishtat, Robert J. ; Anas, Nick ; Meyer, Keith ; Checchia, Paul A. ; Shanley, Thomas P. ; Bigham, Michael T. ; Fitzgerald, Julie ; Banschbach, Sharon ; Beckman, Eileen ; Howard, Kelli ; Frank, Erin ; Harmon, Kelli ; Wong, Hector R. / Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock. In: Critical Care. 2014 ; Vol. 18, No. 6.
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abstract = "Introduction: Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis. Methods: We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1{\%}. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock. Results: In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C. Conclusions: Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.",
author = "Weiss, {Scott L.} and Cvijanovich, {Natalie Z.} and Allen, {Geoffrey L.} and Thomas, {Neal J.} and Freishtat, {Robert J.} and Nick Anas and Keith Meyer and Checchia, {Paul A.} and Shanley, {Thomas P.} and Bigham, {Michael T.} and Julie Fitzgerald and Sharon Banschbach and Eileen Beckman and Kelli Howard and Erin Frank and Kelli Harmon and Wong, {Hector R.}",
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Weiss, SL, Cvijanovich, NZ, Allen, GL, Thomas, NJ, Freishtat, RJ, Anas, N, Meyer, K, Checchia, PA, Shanley, TP, Bigham, MT, Fitzgerald, J, Banschbach, S, Beckman, E, Howard, K, Frank, E, Harmon, K & Wong, HR 2014, 'Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock', Critical Care, vol. 18, no. 6, 623. https://doi.org/10.1186/s13054-014-0623-9

Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock. / Weiss, Scott L.; Cvijanovich, Natalie Z.; Allen, Geoffrey L.; Thomas, Neal J.; Freishtat, Robert J.; Anas, Nick; Meyer, Keith; Checchia, Paul A.; Shanley, Thomas P.; Bigham, Michael T.; Fitzgerald, Julie; Banschbach, Sharon; Beckman, Eileen; Howard, Kelli; Frank, Erin; Harmon, Kelli; Wong, Hector R.

In: Critical Care, Vol. 18, No. 6, 623, 19.11.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock

AU - Weiss, Scott L.

AU - Cvijanovich, Natalie Z.

AU - Allen, Geoffrey L.

AU - Thomas, Neal J.

AU - Freishtat, Robert J.

AU - Anas, Nick

AU - Meyer, Keith

AU - Checchia, Paul A.

AU - Shanley, Thomas P.

AU - Bigham, Michael T.

AU - Fitzgerald, Julie

AU - Banschbach, Sharon

AU - Beckman, Eileen

AU - Howard, Kelli

AU - Frank, Erin

AU - Harmon, Kelli

AU - Wong, Hector R.

PY - 2014/11/19

Y1 - 2014/11/19

N2 - Introduction: Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis. Methods: We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock. Results: In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C. Conclusions: Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.

AB - Introduction: Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis. Methods: We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock. Results: In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C. Conclusions: Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.

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Weiss SL, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ, Anas N et al. Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock. Critical Care. 2014 Nov 19;18(6). 623. https://doi.org/10.1186/s13054-014-0623-9