Proteostasis failure and mitochondrial dysfunction leads to aneuploidy-induced senescence

Joy, Jery; Barrio, Lara; Santos-Tapia, Celia; Romão, Daniela; Giakoumakis, Nickolaos Nikiforos; Clemente‐Ruiz, Marta; Milán, Marco

doi:10.1016/j.devcel.2021.06.009

Cited by 38 publications

(28 citation statements)

References 79 publications

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“…49 In a Drosophila epithelial model, JNK (c-Jun N-terminal kinase) plays a role in driving senescence as a consequence of dysfunctional mitochondria and ROS. 50 There is increasing evidence that the connection site between ER and mitochondria serves as an important cell signaling platform, for processes including calcium ion storage, lipid biosynthesis, mitochondrial division and autophagy induction. [51][52][53][54] The ER membrane protein BAP31 is a key factor for mitochondrial homeostasis and it regulates mitochondrial function via the interaction with Tom40 within the ER-mitochondria contact sites.…”

Section: Papermentioning

confidence: 99%

Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions

et al. 2022

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Section: Papermentioning

confidence: 99%

Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions

et al. 2022

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“…Cellular senescence can be induced by various stressors including mitochondrial dysfunction, autophagy dysfunction, oxidative stress and telomere erosion [ 10 – 12 ]. Mitochondria undergo mitochondrial fission, mediated by dynamin-related protein 1 (Drp1) and fission 1 (Fis1), and fusion, regulated by Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2) and optic atrophy protein 1 (OPA1), to maintain their function.…”

Section: Introductionmentioning

confidence: 99%

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence

et al. 2021

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Background Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. Methods MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-β-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence Results EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. Conclusion Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction. Graphic abstract

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“…ROS overload was widely found during mitochondrial dysfunction, mediating multiple signaling pathways, such as JNK, to engender cell senescence. 360 For example, mitochondrial DNA double strand break‐mediated ROS generation accelerated the aging of certain tissues, which can be partially attributed to the activation of cell cycle arrest proteins (p21/p53 pathway). 361 Thus, there is a positive feedback loop of the aging‐ROS‐mitochondrial dysfunction‐ROS axis, indicating a great potential of modulating ROS levels for attenuating aging (Figure 8 ).…”

Section: Redox Imbalance and Oxidative Damage In Human Diseasementioning

confidence: 99%

Redox signaling at the crossroads of human health and disease

Zuo

Zhang

Luo

et al. 2022

MedComm

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Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double‐edged sword in disease progression suggest two different therapeutic strategies to treat redox‐relevant diseases, in which targeting ROS sources and redox‐related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox‐relevant diseases.

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Proteostasis failure and mitochondrial dysfunction leads to aneuploidy-induced senescence

Cited by 38 publications

References 79 publications

Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions

Resveratrol drives cancer cell senescence via enhancing p38MAPK and DLC1 expressions

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence

Redox signaling at the crossroads of human health and disease

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