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

作     者：Sieprath, Tom Corne, Tobias D. J. Nooteboom, Marco Grootaert, Charlotte Rajkovic, Andreja Buysschaert, Benjamin Robijns, Joke Broers, Jos L. V. Ramaekers, Frans C. S. Koopman, Werner J. H. Willems, Peter H. G. M. De Vos, Winnok H. 

作者机构：Univ Antwerp Lab Cell Biol & Histol Dept Vet Sci B-2020 Antwerp Belgium Univ Ghent Cell Syst & Imaging Res Grp CSI Dept Mol Biotechnol B-9000 Ghent Belgium Radboud Univ Nijmegen Dept Biochem 286 Radboud Inst Mol Life Sci Med Ctr NL-6525 ED Nijmegen Netherlands Univ Ghent Lab Food Chem & Human Nutr B-9000 Ghent Belgium Univ Ghent Lab Food Microbiol & Food Preservat B-9000 Ghent Belgium Univ Ghent Lab Microbial Ecol & Technol LabMET B-9000 Ghent Belgium Maastricht Univ Dept Mol Cell Biol CARIM Sch Cardiovasc Dis Med Ctr Maastricht Netherlands Maastricht Univ GROW Sch Oncol & Dev Biol Med Ctr Maastricht Netherlands 

出 版 物：《NUCLEUS》 (细胞核)

年 卷 期：2015年第6卷第3期

页      面：236-246页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 071009[理学-细胞生物学] 09[农学] 0901[农学-作物学] 090102[农学-作物遗传育种] 

基　　金：University of Antwerp [TTBOF/29267] Ghent University [BOF/11267/09] Hercules foundation [AUGE/013] NB-Photonics [01-MR0110] CSBR (Centers for Systems Biology Research) initiative from the Netherlands Organization for Scientific Research (NWO) [CSBR09/013V] 

主　　题：apoptosis high-content microscopy lamin A C laminopathies mitochondria mitochondrial dysfunction oxidative stress prelamin A senescence ZMPSTE24 

摘      要：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.