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 language | English |
|---|---|
| Pages (from-to) | 357-365 |
| Number of pages | 9 |
| Journal | Neurobiology of Disease |
| Volume | 34 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - May 2009 |
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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 journal › Article
}
TY - JOUR
T1 - Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia
AU - Silva, Jillian M.
AU - Wong, Alice
AU - Carelli, Valerio
AU - Cortopassi, Gino A.
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
KW - Complex I
KW - Integrated stress response
KW - LHON
KW - Mitochondria
KW - Oligodendroglia
KW - Retrograde signaling
UR - http://www.scopus.com/inward/record.url?scp=64449083860&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=64449083860&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2009.02.005
DO - 10.1016/j.nbd.2009.02.005
M3 - Article
C2 - 19233273
AN - SCOPUS:64449083860
VL - 34
SP - 357
EP - 365
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 2
ER -