Document Type

Journal Article

Publication Date

1-1-2014

Journal

Critical Care

Volume

18

Issue

6

Inclusive Pages

623

DOI

10.1186/s13054-014-0623-9

Keywords

Cell Nucleus--genetics; Gene Expression Regulation; Genome-Wide Association Study--method; Mitochondria--genetrics; Shock, Septic--genetics; Transcriptome--genetics

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.

Comments

Reproduced with permission of BioMed Central Ltd. Critical Care.

Peer Reviewed

1

Open Access

1

Additional Files
Table S1.doc (135 kB)
Table S1
Table S2.doc (61 kB)
Table S2
Table S3.doc (47 kB)
Table S3
Table S4.doc (46 kB)
Table S4
Table S5.doc (150 kB)
Table S5
Table S6.doc (59 kB)
Table S6
Download

Included in

Pediatrics Commons

Share

COinS