Transcriptional changes in OXPHOS complex I deficiency are related to anti-oxidant pathways and could explain the disturbed calcium homeostasis.
Defective complex I (CI) is the most common type of oxidative phosphorylation disease, with an incidence of 1 in 5000 live births. Here, whole genome expression profiling of fibroblasts from CI deficient patients was performed to gain insight into the cell pathological mechanism. Our results suggest that patient fibroblasts responded to oxidative stress by Nrf2-mediated induction of the glutathione antioxidant system and Gadd45-mediated activation of the DNA damage response pathway. Furthermore, the observed reduced expression of selenoproteins, might explain the disturbed calcium homeostasis previously described for the patient fibroblasts and might be linked to endoplasmic reticulum stress. These results suggest that both glutathione and selenium metabolism are potentially therapeutic targets in CI deficiency.
Department of Genetics and Cell Biology, Maastricht University, Maastricht, The Netherlands.
A M
AM
Voets
M
M
Huigsloot
P J
PJ
Lindsey
A M
AM
Leenders
W J H
WJ
Koopman
P H G M
PH
Willems
R J
RJ
Rodenburg
J A M
JA
Smeitink
H J M
HJ
Smeets
D000975:Antioxidants / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002675:Child, Preschool; D004249:DNA Damage; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D051140:Selenoproteins / Q000378:metabolism; D000097642:GADD45 Proteins
D000975:Antioxidants; D002118:Calcium; D018797:Cell Cycle Proteins; D042967:Electron Transport Complex I; D005978:Glutathione; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D051140:Selenoproteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins