Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates
Publication year
2015Source
Nucleus, 6, 3, (2015), pp. 236-46ISSN
Publication type
Article / Letter to editor

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Organization
Biochemistry (UMC)
Journal title
Nucleus
Volume
vol. 6
Issue
iss. 3
Page start
p. 236
Page end
p. 46
Subject
Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life SciencesAbstract
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 (Deltapsim) 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 Deltapsim 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 Deltapsim 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.
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- Academic publications [227864]
- Electronic publications [107343]
- Faculty of Medical Sciences [86218]
- Open Access publications [76463]
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