DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

Hitomi, Kazuhiro; Okada, Ryo; Loo, Tze Mun; Miyata, Kenichi; Nakamura, Asako; Takahashi, Akiko

doi:10.3390/ijms21103720

Cited by 49 publications

(39 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Changes in N-SMase levels have been reported in aging tissues [ 137 ]. A recent study has suggested that upregulation of N-SMase and ceramide biosynthesis contributed to the production of extracellular vesicles and prevented excessive inflammatory response [ 138 ]. However, the exact mechanism of how N-SMase activity contributes to senescence, whether it affects membrane dynamics or generates ceramides at certain membrane locales, is not known and is likely to be tissue specific.…”

Section: Various Lipid Classes Have Been Linked To Senescencementioning

confidence: 99%

Lipid Players of Cellular Senescence

Millner

Atilla‐Gokcumen

2020

Metabolites

View full text Add to dashboard Cite

Lipids are emerging as key players of senescence. Here, we review the exciting new findings on the diverse roles of lipids in cellular senescence, most of which are enabled by the advancements in omics approaches. Senescence is a cellular process in which the cell undergoes growth arrest while retaining metabolic activity. At the organismal level, senescence contributes to organismal aging and has been linked to numerous diseases. Current research has documented that senescent cells exhibit global alterations in lipid composition, leading to extensive morphological changes through membrane remodeling. Moreover, senescent cells adopt a secretory phenotype, releasing various components to their environment that can affect the surrounding tissue and induce an inflammatory response. All of these changes are membrane and, thus, lipid related. Our work, and that of others, has revealed that fatty acids, sphingolipids, and glycerolipids are involved in the initiation and maintenance of senescence and its associated inflammatory components. These studies opened up an exciting frontier to investigate the deeper mechanistic understanding of the regulation and function of these lipids in senescence. In this review, we will provide a comprehensive snapshot of the current state of the field and share our enthusiasm for the prospect of potential lipid-related protein targets for small-molecule therapy in pathologies involving senescence and its related inflammatory phenotypes.

show abstract

Section: Various Lipid Classes Have Been Linked To Senescencementioning

confidence: 99%

Lipid Players of Cellular Senescence

Millner

Atilla‐Gokcumen

2020

Metabolites

View full text Add to dashboard Cite

show abstract

“…It was previously reported that SASP triggers senescence of the surrounding normal cells (51,52). Many studies have focused on these secreted factors and their proposed mechanism in bone metabolism (12,53).…”

Section: Discussionmentioning

confidence: 99%

Radiation induces primary osteocyte senescence phenotype and affects osteoclastogenesis in vitro

Wang

et al. 2021

Int J Mol Med

View full text Add to dashboard Cite

Irradiation-induced bone remodeling imbalances arise as a consequence of the dysregulation of bone formation and resorption. due to the abundance of osteocytes, their long life and their dual-regulatory effects on both osteoblast and osteoclast function, they serve as critical coordinators of bone remolding. In the present study, femur and tibia-derived primary osteocytes were cultured and irradiated to observe the functional changes and the cellular senescence phenotype in vitro. Irradiation directly reduced cell viability, affected the crucial dendritic morphology and altered the expression of functional proteins, including upregulation of receptor activator of nuclear factor-κB ligand and sclerostin, and downregulation of osteoprotegerin. Irradiated osteocytes were shown to exhibit notable dNA damage, which resulted in the initiation of a typical cellular senescence phenotype. Furthermore, it was found that irradiation-induced prematurely senescent osteocytes stimulate molecular secretion, referred to as senescence-associated secretory phenotype (SASP), which may be involved in modulation of the bone microenvironment, including the promotion of osteoclastogenesis. Taken together, the results showed that irradiation triggered osteocyte senescence and the acquisition of an associated secretory phenotype. This further resulted in an imbalance of bone remodeling through senescent influence on proliferation, morphology and marker protein production, but also indirectly via a paracrine pathway through SASP secretion. The results of the present study may highlight the potential of SASP-targeted interventions for the management of radiation-induced bone loss.

show abstract

“… 254 Oxidative stress induces DNA damage, which in turn activates the ceramide synthesis pathway leading to an increase in senescence-associated EV (SA-EV) biogenesis. 107 Latent membrane protein 1 (LMP1) is a viral protein that contributes to the modification of EV content and remodeling of the tumor microenvironment. LMP1 enhances EV production by utilizing LMP1-interacting proteins, including Hrs, Syntenin-1, and the ESCRT-III complex.…”

Section: Promotion Of Evs Releasementioning

confidence: 99%

“…105 Leptin regulates the mechanisms of biogenesis and release of exosomes and also increased the number of MVBs and release of MVBs in the cytoplasm of breast cancer cells. 106 Hitomi et al reported that DNA damage activates the ceramide synthetic pathway leading to an increase in senescence-associated EVs (SA-EV) biogenesis 107 The EVs biogenesis pathway, which is associated with the autophagy-mediated degradation pathway, leads to inhibition of apoptosis. The SA-EV pathway may play a significant role in cellular homeostasis, particularly in senescent cells.…”

mentioning

confidence: 99%

Biogenesis, Membrane Trafficking, Functions, and Next Generation Nanotherapeutics Medicine of Extracellular Vesicles

Gurunathan¹,

Kang²,

Qasim³

et al. 2021

IJN

View full text Add to dashboard Cite

Extracellular vesicles (EVs) are a heterogeneous group of membrane-limited vesicles and multi-signal messengers loaded with biomolecules. Exosomes and ectosomes are two different types of EVs generated by all cell types. Their formation depends on local microdomains assembled in endocytic membranes for exosomes and in the plasma membrane for ectosomes. Further, EV release is a fundamental process required for intercellular communication in both normal physiology and pathological conditions to transmit/exchange bioactive molecules to recipient cells and the extracellular environment. The unique structure and composition of EVs enable them to serve as natural nanocarriers, and their physicochemical properties and biological functions can be used to develop next-generation nano and precision medicine. Knowledge of the cellular processes that govern EVs biology and membrane trafficking is essential for their clinical applications. However, in this rapidly expanding field, much remains unknown regarding EV origin, biogenesis, cargo sorting, and secretion, as well as EV-based theranostic platform generation. Hence, we present a comprehensive overview of the recent advances in biogenesis, membrane trafficking, and functions of EVs, highlighting the impact of nanoparticles and oxidative stress on EVs biogenesis and release and finally emphasizing the role of EVs as nanotherapeutic agents.

show abstract

DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

Cited by 49 publications

References 73 publications

Lipid Players of Cellular Senescence

Lipid Players of Cellular Senescence

Radiation induces primary osteocyte senescence phenotype and affects osteoclastogenesis in vitro

Biogenesis, Membrane Trafficking, Functions, and Next Generation Nanotherapeutics Medicine of Extracellular Vesicles

Contact Info

Product

Resources

About