title: Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts.
abstract: Mutations in gene products expressed in the mitochondrion cause a nuclear transcriptional response that leads to neurological disease. To examine the extent to which the transcriptional profile was shared among 5 mitochondrial diseases (LHON, FRDA, MELAS, KSS, and NARP), we microarrayed mutant and control groups in N-tera2, SH-SY5Y, lymphoblasts, fibroblasts, myoblasts, muscle, and osteosarcoma cybrids. Many more transcripts were observed to be significantly altered and shared among these 5 mitochondrial diseases and cell types than expected on the basis of random chance, and these genes are significantly clustered with respect to biochemical pathways. Mitochondrial disease activated multiple transcripts of the unfolded protein response (UPR), and of the cell cycle pathway, and low doses of the mitochondrial inhibitor rotenone induced UPR transcripts in the absence of cell death. By contrast, functional clusters inhibited by mitochondrial disease included: vesicular secretion, protein synthesis, and oligodendrogenesis. As it is known that UPR activation specifically inhibits vesicular secretion and protein synthesis, these data support the view that mitochondrial disease and dysfunction triggers the UPR, which in turn causes secretory defects which inhibit cellular migratory, synaptic, and oligodendrocytic functions, providing a testable hypothesis for how mitochondrial dysfunction causes disease. Since ischemic hypoxia, chemical hypoxia, and mitochondrial genetic disease (which could be considered 'genetic hypoxia') produce an overlapping induction of UPR and cell cycle genes which appears to have negative consequences, the modulation of these responses might be of benefit to patients with mitochondrial disease.
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Davis, CA 95616, USA. gacortopassi@ucdavis.edu
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
authors.forename: Steven
authors.initials: S
authors.lastname: Danielson
authors.forename: Mansour
authors.initials: M
authors.lastname: Alemi
authors.forename: Shan Shan
authors.initials: SS
authors.lastname: Zhan
authors.forename: Warren
authors.initials: W
authors.lastname: Tong
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinuzzi
authors.forename: Sangot
authors.initials: S
authors.lastname: Marzuki
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
authors.forename: Alice
authors.initials: A
authors.lastname: Wong
mesh_terms: D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D042381:Granulocyte Precursor Cells / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000502:physiology; D053858:Metabolic Networks and Pathways; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D032342:Muscle Cells / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins