title: Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock.
abstract: BACKGROUND
  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.
authors.affiliation: Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA. WeissS@email.chop.edu.|Center for Resuscitation Science, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA. WeissS@email.chop.edu.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.affiliation: UCSF Benioff Children's Hospital Oakland, 1411 East 31st Street, Oakland, CA, 94602, USA. NCvijanovich@mail.cho.org.
authors.forename: Natalie Z
authors.initials: NZ
authors.lastname: Cvijanovich
authors.affiliation: Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO, 64108, USA. glallen@cmh.edu.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Allen
authors.affiliation: Penn State Children's Hospital, 500 University Drive, Hershey, PA, 17033, USA. nthomas@hmc.psu.edu.
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Thomas
authors.affiliation: Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, 20010, USA. RFreishtat@childrensnational.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.affiliation: Children's Hospital of Orange County, 1201 W La Veta Avenue, Orange, CA, 92868, USA. nanas@choc.org.
authors.forename: Nick
authors.initials: N
authors.lastname: Anas
authors.affiliation: Miami Children's Hospital, 3100 SW 62nd Avenue, Miami, FL, 33155, USA. Keith.Meyer@mch.com.
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Texas Children's Hospital, 6621 Fannin Street, Houston, TX, 77030, USA. pachecch@texaschildrens.org.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Checchia
authors.affiliation: CS Mott Children's Hospital at the University of Michigan, 1540 E Hospital Drive, Ann Arbor, MI, 48109, USA. tshanley@med.umich.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
authors.affiliation: Akron Children's Hospital, 1 Perkins Square, Akron, OH, 44302, USA. mbigham@chmca.org.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bigham
authors.affiliation: Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA. FitzgeraldJ@email.chop.edu.
authors.forename: Julie
authors.initials: J
authors.lastname: Fitzgerald
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. sharon.banschbach@cchmc.org.
authors.forename: Sharon
authors.initials: S
authors.lastname: Banschbach
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. eileen.beckman@cchmc.org.
authors.forename: Eileen
authors.initials: E
authors.lastname: Beckman
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. kelli.howard@cchmc.org.
authors.forename: Kelli
authors.initials: K
authors.lastname: Howard
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. erin.frank@cchmc.org.
authors.forename: Erin
authors.initials: E
authors.lastname: Frank
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. kelli.harmon@cchmc.org.
authors.forename: Kelli
authors.initials: K
authors.lastname: Harmon
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA. hector.wong@cchmc.org.|Department of Pediatrics, University of Cincinnati College of Medicine, 3230 Eden Avenue, Cincinnati, OH, 45267, USA. hector.wong@cchmc.org.
authors.forename: Hector R
authors.initials: HR
authors.lastname: Wong
mesh_terms: D002467:Cell Nucleus / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D012772:Shock, Septic / Q000175:diagnosis / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*