Title
Sustained accumulation of prelamin a and depletion of lamin a/c both cause oxidative stress and mitochondrial dysfunction but induce different cell fatesSustained accumulation of prelamin a and depletion of lamin a/c both cause oxidative stress and mitochondrial dysfunction but induce different cell fates
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Research group
Laboratory of cell biology and histology
Publication type
article
Publication
Subject
Biology
Veterinary medicine
Human medicine
Source (journal)
Nucleus
Volume/pages
6(2015):3, p. 236-246
ISSN
1949-1034
ISI
000357866200011
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
The cell nucleus is structurally and functionally organized by lamins, intermediate filament proteins that form the nuclear lamina. Point mutations in genes that encode a specific subset of lamins, the A-type lamins, cause a spectrum of diseases termed laminopathies. Recent evidence points to a role for A-type lamins in intracellular redox homeostasis. To determine whether lamin A/C depletion and prelamin A accumulation differentially induce oxidative stress, we have performed a quantitative microscopy-based analysis of reactive oxygen species (ROS) levels and mitochondrial membrane potential (Δψμ) in human fibroblasts subjected to sustained siRNA-mediated knockdown of LMNA and ZMPSTE24, respectively. We measured a highly significant increase in basal ROS levels and an even more prominent rise of induced ROS levels in lamin A/C depleted cells, eventually resulting in Δψμ hyperpolarization and apoptosis. Depletion of ZMPSTE24 on the other hand, triggered a senescence pathway that was associated with moderately increased ROS levels and a transient Δψμ depolarization. Both knockdowns were accompanied by an upregulation of several ROS detoxifying enzymes. Taken together, our data suggest that both persistent prelamin A accumulation and lamin A/C depletion elevate ROS levels, but to a different extent and with different effects on cell fate. This may contribute to the variety of disease phenotypes witnessed in laminopathies.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/18e5b5/01225841.pdf
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