Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia
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...
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doaj-0ef2ac40119e46dcacec12547e062b1c2021-03-20T04:57:14ZengElsevierNeurobiology of Disease1095-953X2009-05-01342357365Inhibition of mitochondrial function induces an integrated stress response in oligodendrogliaJillian M. Silva0Alice Wong1Valerio Carelli2Gino A. Cortopassi3Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USADepartment of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USAThe Institute of Neurology, University of Bologna, 40123 Bologna, ItalyDepartment of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USA; Corresponding author. Fax. +1 530 754 9342.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.http://www.sciencedirect.com/science/article/pii/S0969996109000333Integrated stress responseMitochondriaComplex ILHONRetrograde signalingOligodendroglia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jillian M. Silva Alice Wong Valerio Carelli Gino A. Cortopassi |
spellingShingle |
Jillian M. Silva Alice Wong Valerio Carelli Gino A. Cortopassi Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia Neurobiology of Disease Integrated stress response Mitochondria Complex I LHON Retrograde signaling Oligodendroglia |
author_facet |
Jillian M. Silva Alice Wong Valerio Carelli Gino A. Cortopassi |
author_sort |
Jillian M. Silva |
title |
Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia |
title_short |
Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia |
title_full |
Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia |
title_fullStr |
Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia |
title_full_unstemmed |
Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia |
title_sort |
inhibition of mitochondrial function induces an integrated stress response in oligodendroglia |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2009-05-01 |
description |
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. |
topic |
Integrated stress response Mitochondria Complex I LHON Retrograde signaling Oligodendroglia |
url |
http://www.sciencedirect.com/science/article/pii/S0969996109000333 |
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