The Interplay between Oxidative Stress and the Nuclear Lamina Contributes to Laminopathies and Age-Related Diseases

Abstract

Oxidative stress is a physiological condition that arises when there is an imbalance between the production of reactive oxygen species (ROS) and the ability of cells to neutralize them. ROS can damage cellular macromolecules, including lipids, proteins, and DNA, leading to cellular senescence and physiological aging. The nuclear lamina (NL) is a meshwork of intermediate filaments that provides structural support to the nucleus and plays crucial roles in various nuclear functions, such as DNA replication and transcription. Emerging evidence suggests that oxidative stress disrupts the integrity and function of the NL, leading to dysregulation of gene expression, DNA damage, and cellular senescence. This review highlights the current understanding of the interplay between oxidative stress and the NL, along with its implications for human health. Specifically, elucidation of the mechanisms underlying the interplay between oxidative stress and the NL is essential for the development of effective treatments for laminopathies and age-related diseases.

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

“…226 Not only is Nrf2 expression downregulated, but the protein is also sequestered by progerin, minimizing the amount of active Nrf2 to induce target genes. 226 Decreased expression of the lysophosphatidic acid receptor (LPA 3 ) also increases the level of ROS in HGPS model cells. 227 ROS links mutant lamins to other organellar dysfunction in laminopathies.…”

“…However, a contradictory study reported that the level and function of superoxide dismutase (SOD1), CAT, and GSH are increased to the challenges of ROS in laminopathic cells expressing LMNA Y259X . 226 ROS also inhibits the transport of proteins from the cytosol to the nucleus by preventing the activity of RAN in HGPS cells. 230 Hydrogen sulphide (H 2 S) is another modulator of chromatin binding to nuclear lamina.…”

“…Overaccumulation of ROS in laminopathic disease is also associated with deregulation of expression of nuclear factor erythroid 2‐related factor 2 (Nrf2), which functions as a master regulator of ROS detoxifying genes 226 . Not only is Nrf2 expression downregulated, but the protein is also sequestered by progerin, minimizing the amount of active Nrf2 to induce transcription of target genes 226 . Decreased expression of the lysophosphatidic acid receptor (LPA 3 ) also increases the level of ROS in HGPS model cells 227 …”

“…In addition, lower expression of the components of the nucleosome remodeling and deacetylase (NuRD) complex reduces the ability to repair DNA damage in HGPS cells 225 . Overaccumulation of ROS in laminopathic disease is also associated with deregulation of expression of nuclear factor erythroid 2‐related factor 2 (Nrf2), which functions as a master regulator of ROS detoxifying genes 226 . Not only is Nrf2 expression downregulated, but the protein is also sequestered by progerin, minimizing the amount of active Nrf2 to induce transcription of target genes 226 .…”

“…In general, the structure and function of peroxisomes are compromised, 229 so the clearance of ROS is impaired in HGPS. However, a contradictory study reported that the level and function of superoxide dismutase (SOD1), CAT, and GSH are increased to overcome the challenges of ROS in laminopathic cells expressing LMNA Y259X 226 . ROS also inhibits the transport of proteins from the cytosol to the nucleus by preventing the activity of RAN in HGPS cells 230 …”