Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia

Neurobiol Dis. 2009 May;34(2):357-65. doi: 10.1016/j.nbd.2009.02.005. Epub 2009 Feb 20.


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 eIF2alpha 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factor 4 / drug effects
  • Activating Transcription Factor 4 / metabolism
  • Adenosine Triphosphate / biosynthesis
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Respiration / drug effects
  • Cell Respiration / genetics
  • Dose-Response Relationship, Drug
  • Electron Transport Complex I / genetics*
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinase 8 / drug effects
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Optic Atrophy, Hereditary, Leber / genetics
  • Optic Atrophy, Hereditary, Leber / metabolism*
  • Optic Atrophy, Hereditary, Leber / physiopathology
  • Optic Nerve / metabolism*
  • Optic Nerve / pathology
  • Optic Nerve / physiopathology
  • Stress, Physiological / genetics*
  • Transcription Factor CHOP / drug effects
  • Transcription Factor CHOP / metabolism
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism
  • Uncoupling Agents / toxicity
  • eIF-2 Kinase / drug effects
  • eIF-2 Kinase / metabolism


  • ATF4 protein, human
  • DDIT3 protein, human
  • Transcription Factors
  • Uncoupling Agents
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • ELF2 protein, human
  • Adenosine Triphosphate
  • PERK kinase
  • eIF-2 Kinase
  • Mitogen-Activated Protein Kinase 8
  • Electron Transport Complex I