title: Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing.
abstract: Muscle, heart and liver were analyzed in a male subject who succumbed to HSD10 disease. Respiratory chain enzyme analysis and BN-PAGE showed reduced activities and assembly of complexes I, III, IV, and V. The mRNAs of all RNase P subunits were preserved in heart and overexpressed in muscle, but MRPP2 protein was severely decreased. RNase P upregulation correlated with increased expression of mitochondrial biogenesis factors and preserved mitochondrial enzymes in muscle, but not in heart where this compensatory mechanism was incomplete. We demonstrate elevated amounts of unprocessed pre-tRNAs and mRNA transcripts encoding mitochondrial subunits indicating deficient RNase P activity. This study provides evidence of abnormal mitochondrial RNA processing causing mitochondrial energy failure in HSD10 disease.
authors.affiliation: Pediatric Cardiology, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Chatfield
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Coughlin
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Friederich
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Renata C
authors.initials: RC
authors.lastname: Gallagher
authors.affiliation: Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Hesselberth
authors.affiliation: Department of Pathology, University of Colorado, Aurora, CO, USA; Department of Pathology, Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovell
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Swanson
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Thomas
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.affiliation: Department of Pathology, Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Wartchow
authors.affiliation: Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA. Electronic address: Johan.Vanhove@ucdenver.edu.
authors.forename: Johan L K
authors.initials: JL
authors.lastname: Van Hove
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency*; D019069:Cell Respiration; D004272:DNA, Mitochondrial / Q000378:metabolism*; D020820:Dyskinesias; D004579:Electron Transport; D004734:Energy Metabolism; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000503:physiopathology*; D008099:Liver / Q000473:pathology; D008297:Male; D038901:X-Linked Intellectual Disability; D008928:Mitochondria / Q000235:genetics / Q000502:physiology*; D009132:Muscles / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional; D014158:Transcription, Genetic
chemical_list: D004272:DNA, Mitochondrial; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D000101:Acetyl-CoA C-Acetyltransferase
keywords: HSD10 disease; MHBD disease; MRPP2; RNA processing; RNase P