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Title
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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
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Nucleus
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Publication
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2015
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ISSN
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1949-1034
1949-1042
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DOI
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10.1080/19491034.2015.1050568
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Volume/pages
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6
:3
(2015)
, p. 236-246
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ISI
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000357866200011
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Pubmed ID
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25996284
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Full text (Publisher's DOI)
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Full text (open access)
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