title: Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network.
abstract: Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5'-UTRs that likely improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD(+) redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.
authors.affiliation: Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mai
authors.initials: M
authors.lastname: Tsukikawa
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.forename: Erzsebet
authors.initials: E
authors.lastname: Polyak
authors.forename: Eiko
authors.initials: E
authors.lastname: Nakamaru-Ogiso
authors.forename: Julian
authors.initials: J
authors.lastname: Ostrovsky
authors.forename: Shana
authors.initials: S
authors.lastname: McCormack
authors.forename: Emily
authors.initials: E
authors.lastname: Place
authors.forename: Colleen
authors.initials: C
authors.lastname: Clarke
authors.forename: Gail
authors.initials: G
authors.lastname: Reiner
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McCormick
authors.forename: Eric
authors.initials: E
authors.lastname: Rappaport
authors.forename: Richard
authors.initials: R
authors.lastname: Haas
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004579:Electron Transport / Q000235:genetics / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D059467:Transcriptome / Q000235:genetics*; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions
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