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Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates

(2015) NUCLEUS. 6(3). p.236-246
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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 ((m)) 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 (m)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 (m)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.
Keywords
senescence, SENESCENCE, ZMPSTE24, prelamin A, GILFORD-PROGERIA-SYNDROME, mitochondrial dysfunction, laminopathies, GROWTH ARREST, RESTRICTIVE DERMOPATHY, A-TYPE LAMINS, ROS GENERATION, DNA-DAMAGE, apoptosis, high-content microscopy, NUCLEAR-ENVELOPE, mitochondria, oxidative stress, HUMAN FIBROBLASTS, SECRETORY PHENOTYPE, lamin A, C

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Citation

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Chicago
Sieprath, Tom, Tobias Corne, Marco Nooteboom, Charlotte Grootaert, Andreja Rajkovic, Benjamin Buysschaert, Joke Robijns, et al. 2015. “Sustained Accumulation of Prelamin A and Depletion of Lamin A/C Both Cause Oxidative Stress and Mitochondrial Dysfunction but Induce Different Cell Fates.” Nucleus 6 (3): 236–246.
APA
Sieprath, T., Corne, T., Nooteboom, M., Grootaert, C., Rajkovic, A., Buysschaert, B., Robijns, J., et al. (2015). Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates. NUCLEUS, 6(3), 236–246.
Vancouver
1.
Sieprath T, Corne T, Nooteboom M, Grootaert C, Rajkovic A, Buysschaert B, et al. Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates. NUCLEUS. 2015;6(3):236–46.
MLA
Sieprath, Tom, Tobias Corne, Marco Nooteboom, et al. “Sustained Accumulation of Prelamin A and Depletion of Lamin A/C Both Cause Oxidative Stress and Mitochondrial Dysfunction but Induce Different Cell Fates.” NUCLEUS 6.3 (2015): 236–246. Print.
@article{5977785,
  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 ((m)) 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 (m)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 (m)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.},
  author       = {Sieprath, Tom and Corne, Tobias and Nooteboom, Marco and Grootaert, Charlotte and Rajkovic, Andreja and Buysschaert, Benjamin and Robijns, Joke and Broers, Jos LV and Ramaekers, Frans CS and Koopman, Werner JH and Willems, Peter HGM and De Vos, Winnok},
  issn         = {1949-1034},
  journal      = {NUCLEUS},
  keyword      = {senescence,SENESCENCE,ZMPSTE24,prelamin A,GILFORD-PROGERIA-SYNDROME,mitochondrial dysfunction,laminopathies,GROWTH ARREST,RESTRICTIVE DERMOPATHY,A-TYPE LAMINS,ROS GENERATION,DNA-DAMAGE,apoptosis,high-content microscopy,NUCLEAR-ENVELOPE,mitochondria,oxidative stress,HUMAN FIBROBLASTS,SECRETORY PHENOTYPE,lamin A,C},
  language     = {eng},
  number       = {3},
  pages        = {236--246},
  title        = {Sustained accumulation of prelamin A and depletion of lamin A/C both cause oxidative stress and mitochondrial dysfunction but induce different cell fates},
  url          = {http://dx.doi.org/10.1080/19491034.2015.1050568},
  volume       = {6},
  year         = {2015},
}

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