Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia

Jillian M. Silva, Alice Wong, Valerio Carelli, Gino A. Cortopassi

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Maternal inheritance of a pathogenic point mutation within complex I of the mitochondrial genome causes Leber's hereditary optic neuropathy (LHON), resulting in the neurodegeneration and demyelination of the optic nerve. The integrated stress response (ISR), a signaling pathway that responds to various stresses by activating a common set of genes, has been linked to both mitochondrial defects and demyelinating diseases. Therefore, we wanted to determine whether mitochondrial dysfunction induced by complex I inhibition with rotenone can activate the ISR, specifically by the ER kinase PERK, in oligodendroglial cells. Our complex I-deficient oligodendroglial model reproduced similar biochemical defects as in LHON by decreasing ATP synthesis and ATP levels. The same doses of rotenone that reduced ATP production also induced dose-dependent increases in PERK and eIF2α phosphorylation as well as activated the ISR stress genes, ATF4 and CHOP. In addition, complex I inhibition at these same concentrations induced a PERK-dependent activation of the cell death kinase, JNK, and inhibited oligodendroglial proliferation. Taken together, our results demonstrate that activation of the ISR may be one example of mitochondrial retrograde signaling in response to complex I deficiency and we suggest that this response mechanism may be relevant to the pathophysiology of LHON.

Original languageEnglish
Pages (from-to)357-365
Number of pages9
JournalNeurobiology of Disease
Volume34
Issue number2
DOIs
Publication statusPublished - May 2009

Fingerprint

Leber's Hereditary Optic Atrophy
Oligodendroglia
Rotenone
Adenosine Triphosphate
Demyelinating Diseases
MAP Kinase Kinase 4
Mitochondrial Diseases
Mitochondrial Genome
Optic Nerve
Point Mutation
Genes
Cell Death
Phosphorylation

Keywords

  • Complex I
  • Integrated stress response
  • LHON
  • Mitochondria
  • Oligodendroglia
  • Retrograde signaling

ASJC Scopus subject areas

  • Neurology

Cite this

Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. / Silva, Jillian M.; Wong, Alice; Carelli, Valerio; Cortopassi, Gino A.

In: Neurobiology of Disease, Vol. 34, No. 2, 05.2009, p. 357-365.

Research output: Contribution to journalArticle

Silva, Jillian M. ; Wong, Alice ; Carelli, Valerio ; Cortopassi, Gino A. / Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. In: Neurobiology of Disease. 2009 ; Vol. 34, No. 2. pp. 357-365.
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