Premium
Mitochondrial inhibition induces PERK‐dependent activation of the unfolded protein response stress pathway in human oligodendroglial cells
Author(s) -
Silva Jillian M,
Wong Alice,
Cortopassi Gino A
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.303
Subject(s) - atf4 , unfolded protein response , integrated stress response , protein kinase r , microbiology and biotechnology , neurodegeneration , biology , eif 2 kinase , mitochondrion , protein kinase a , activating transcription factor , rotenone , kinase , genetics , endoplasmic reticulum , cyclin dependent kinase 2 , medicine , translation (biology) , disease , messenger rna , gene
Maternal inheritance of a point mutation within complex I of the mitochondrial genome causes Leber's hereditary optic neuropathy (LHON), a disease that results in the neurodegeneration and demyelination of the optic nerve leading to blindness. Previous studies have shown that mitochondrial DNA mutations can activate the unfolded protein response (UPR), a signaling pathway that responds to ER stress (PERK→eIF2α→ATF4→CHOP). We used a specific complex I inhibitor, rotenone, to simulate the LHON mutations in human oligodendroglial (HOG) cells in order to study the mechanism of PKR‐like ER kinase (PERK)‐induced UPR activation as a possible pathophysiological consequence in LHON. Mitochondrial inhibition with rotenone in HOGs reproduced the biochemical defects in LHON by significantly decreasing ATP synthesis and ATP levels. Our data demonstrates that rotenone caused dose‐dependent increases in phosphorylation of PERK and eIF2α as well as rotenone‐dependent activation of the downstream translational and transcriptional targets, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). In addition, rotenone dose‐dependently induced phosphorylation of the apoptotic kinase, c‐Jun‐N‐terminal kinase (JNK). Taken together, these results suggest that mitochondrial inhibition can elicit an ER stress response that may lead to cell death and contribute to the pathology of LHON.