Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts

Gino Cortopassi, Steven Danielson, Mansour Alemi, Shan Shan Zhan, Warren Tong, Valerio Carelli, Andrea Martinuzzi, Sangot Marzuki, Kari Majamaa, Alice Wong

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)161-175
Number of pages15
JournalMitochondrion
Volume6
Issue number4
DOIs
Publication statusPublished - Aug 2006

Fingerprint

Unfolded Protein Response
Mitochondrial Diseases
Oligodendroglia
Cell Cycle
MELAS Syndrome
Rotenone
cdc Genes
Inborn Genetic Diseases
Myoblasts
Osteosarcoma
Genes
Mitochondria
Proteins
Cell Death
Fibroblasts
Muscles
Control Groups
Mutation

Keywords

  • Microarray
  • Mitochondrial genetic disease
  • Unfolded protein response

ASJC Scopus subject areas

  • Biophysics

Cite this

Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts. / Cortopassi, Gino; Danielson, Steven; Alemi, Mansour; Zhan, Shan Shan; Tong, Warren; Carelli, Valerio; Martinuzzi, Andrea; Marzuki, Sangot; Majamaa, Kari; Wong, Alice.

In: Mitochondrion, Vol. 6, No. 4, 08.2006, p. 161-175.

Research output: Contribution to journalArticle

Cortopassi, Gino ; Danielson, Steven ; Alemi, Mansour ; Zhan, Shan Shan ; Tong, Warren ; Carelli, Valerio ; Martinuzzi, Andrea ; Marzuki, Sangot ; Majamaa, Kari ; Wong, Alice. / Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts. In: Mitochondrion. 2006 ; Vol. 6, No. 4. pp. 161-175.
@article{b39f791526f84fd190fa6c6ef16c6e35,
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.",
keywords = "Microarray, Mitochondrial genetic disease, Unfolded protein response",
author = "Gino Cortopassi and Steven Danielson and Mansour Alemi and Zhan, {Shan Shan} and Warren Tong and Valerio Carelli and Andrea Martinuzzi and Sangot Marzuki and Kari Majamaa and Alice Wong",
year = "2006",
month = "8",
doi = "10.1016/j.mito.2006.05.002",
language = "English",
volume = "6",
pages = "161--175",
journal = "Mitochondrion",
issn = "1567-7249",
publisher = "Elsevier",
number = "4",

}

TY - JOUR

T1 - Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts

AU - Cortopassi, Gino

AU - Danielson, Steven

AU - Alemi, Mansour

AU - Zhan, Shan Shan

AU - Tong, Warren

AU - Carelli, Valerio

AU - Martinuzzi, Andrea

AU - Marzuki, Sangot

AU - Majamaa, Kari

AU - Wong, Alice

PY - 2006/8

Y1 - 2006/8

N2 - 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.

AB - 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.

KW - Microarray

KW - Mitochondrial genetic disease

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=33748154507&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748154507&partnerID=8YFLogxK

U2 - 10.1016/j.mito.2006.05.002

DO - 10.1016/j.mito.2006.05.002

M3 - Article

C2 - 16815102

AN - SCOPUS:33748154507

VL - 6

SP - 161

EP - 175

JO - Mitochondrion

JF - Mitochondrion

SN - 1567-7249

IS - 4

ER -