bims-cesemi 2024-09-15 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–09–15
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence.
Mitochondrial RNA cytosolic leakage drives the SASP.
Systematic transcriptomic analysis and temporal modelling of human fibroblast senescence.
Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren's disease.
Transiently formed nucleus-to-cilium microtubule arrays mediate senescence initiation in a KIFC3-dependent manner.
Bazi Bushen mitigates age-related muscular atrophy by alleviating cellular senescence of skeletal muscle.
Impaired Incorporation of Fibronectin into the Extracellular Matrix during Aging Exacerbates the Senescent State of Dermal Cells.
Metformin and its potential influence on cell fate decision between apoptosis and senescence in cancer, with a special emphasis on glioblastoma.

EMBO J. 2024 Sep 11.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.

  The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics

DOI:  https://doi.org/10.1038/s44318-024-00219-w
Redox Biol. 2024 Sep 06. pii: S2213-2317(24)00322-7. [Epub ahead of print]76 103344

CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence.

Yena Cho, Yong Kee Kim.

  CARM1 is predominantly localized in the nucleus and plays a pivotal role in maintaining mitochondrial homeostasis by regulating gene expression. It suppresses mitochondrial biogenesis by downregulating PGC-1α and TFAM expression, while promoting mitochondrial fission through increased DNM1L expression. Under oxidative stress, CARM1 translocates to the cytoplasm, where it directly methylates DRP1 and accelerates mitochondrial fission, enhancing reactive oxygen species (ROS) production. Cytoplasmic localization of CARM1 is facilitated by its phosphorylation at S595 by ROS-activated p38γ MAPK, creating a positive feedback loop. Consequently, cytoplasmic CARM1 contributes to cellular senescence by altering mitochondrial dynamics and increasing ROS levels. This observation was supported by the increased cytoplasmic CARM1 levels and disrupted mitochondrial dynamics in the transformed 10T1/2 cells. Moreover, CARM1 inhibitors not only inhibit the proliferation of cancer cells but also induce apoptotic death in senescent cells. These findings highlight the potential of CARM1 inhibitors, particularly those targeting cytoplasmic functions, as novel strategies for eliminating cancer and senescent cells.

Keywords:  CARM1; Mitochondrial homeostasis; ROS; Senescence; p38γ MAPK

DOI:  https://doi.org/10.1016/j.redox.2024.103344
Res Sq. 2024 Aug 27. pii: rs.3.rs-4876596. [Epub ahead of print]

Mitochondrial RNA cytosolic leakage drives the SASP.

Stella Victorelli, Madeline Eppard, Seung-Hwa Woo, Stacia Everts, Helene Martini, Nicholas Pirius, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Patrick Splinter, Steven O'Hara, Lucia Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas LaRusso, Petra Hirsova, Joao Passos.

Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK plays a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-4876596/v1
Front Aging. 2024 ;5 1448543

Systematic transcriptomic analysis and temporal modelling of human fibroblast senescence.

R-L Scanlan, L Pease, H O'Keefe, A Martinez-Guimera, L Rasmussen, J Wordsworth, D Shanley.

  Cellular senescence is a diverse phenotype characterised by permanent cell cycle arrest and an associated secretory phenotype (SASP) which includes inflammatory cytokines. Typically, senescent cells are removed by the immune system, but this process becomes dysregulated with age causing senescent cells to accumulate and induce chronic inflammatory signalling. Identifying senescent cells is challenging due to senescence phenotype heterogeneity, and senotherapy often requires a combinatorial approach. Here we systematically collected 119 transcriptomic datasets related to human fibroblasts, forming an online database describing the relevant variables for each study allowing users to filter for variables and genes of interest. Our own analysis of the database identified 28 genes significantly up- or downregulated across four senescence types (DNA damage induced senescence (DDIS), oncogene induced senescence (OIS), replicative senescence, and bystander induced senescence) compared to proliferating controls. We also found gene expression patterns of conventional senescence markers were highly specific and reliable for different senescence inducers, cell lines, and timepoints. Our comprehensive data supported several observations made in existing studies using single datasets, including stronger p53 signalling in DDIS compared to OIS. However, contrary to some early observations, both p16 and p21 mRNA levels rise quickly, depending on senescence type, and persist for at least 8-11 days. Additionally, little evidence was found to support an initial TGFβ-centric SASP. To support our transcriptomic analysis, we computationally modelled temporal protein changes of select core senescence proteins during DDIS and OIS, as well as perform knockdown interventions. We conclude that while universal biomarkers of senescence are difficult to identify, conventional senescence markers follow predictable profiles and construction of a framework for studying senescence could lead to more reproducible data and understanding of senescence heterogeneity.

Keywords:  big data; cellular senescence; computational model; fibroblast; temporal profile; transcriptomic

DOI:  https://doi.org/10.3389/fragi.2024.1448543
Elife. 2024 Sep 11. pii: RP97069. [Epub ahead of print]13

Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren's disease.

Kai-Ting Huang, Larry E Wagner, Takahiro Takano, Xiao-Xuan Lin, Harini Bagavant, Umesh Deshmukh, David I Yule.

  The molecular mechanisms leading to saliva secretion are largely established, but factors that underlie secretory hypofunction, specifically related to the autoimmune disease Sjögren's syndrome (SS) are not fully understood. A major conundrum is the lack of association between the severity of salivary gland immune cell infiltration and glandular hypofunction. SS-like disease was induced by treatment with DMXAA, a small molecule agonist of murine STING. We have previously shown that the extent of salivary secretion is correlated with the magnitude of intracellular Ca2+ signals (Takano et al., 2021). Contrary to our expectations, despite a significant reduction in fluid secretion, neural stimulation resulted in enhanced Ca2+ signals with altered spatiotemporal characteristics in vivo. Muscarinic stimulation resulted in reduced activation of the Ca2+-activated Cl- channel, TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+. Super-resolution microscopy revealed a disruption in the colocalization of Inositol 1,4,5-trisphosphate receptor Ca2+ release channels with TMEM16a, and channel activation was reduced when intracellular Ca2+ buffering was increased. These data indicate altered local peripheral coupling between the channels. Appropriate Ca2+ signaling is also pivotal for mitochondrial morphology and bioenergetics. Disrupted mitochondrial morphology and reduced oxygen consumption rate were observed in DMXAA-treated animals. In summary, early in SS disease, dysregulated Ca2+ signals lead to decreased fluid secretion and disrupted mitochondrial function contributing to salivary gland hypofunction.

Keywords:  Ca2+ signaling; IP3R; Sjogrens diseas; TMEM16a; cell biology; mitochondria; mouse; xerostomia

DOI:  https://doi.org/10.7554/eLife.97069
Nat Commun. 2024 Sep 12. 15(1): 7977

Transiently formed nucleus-to-cilium microtubule arrays mediate senescence initiation in a KIFC3-dependent manner.

Jielu Hao Robichaud, Yingyi Zhang, Chuan Chen, Kai He, Yan Huang, Xu Zhang, Xiaobo Sun, Xiaoyu Ma, Gary Hardyman, Ciaran G Morrison, Zheng Dong, Nathan K LeBrasseur, Kun Ling, Jinghua Hu.

Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells.

DOI: https://doi.org/10.1038/s41467-024-52363-w
J Tradit Complement Med. 2024 Sep;14(5): 510-521

Bazi Bushen mitigates age-related muscular atrophy by alleviating cellular senescence of skeletal muscle.

Kunxu Niu, Liping Chang, Runtao Zhang, Yuning Jiang, Xiaogang Shen, Xuan Lu, Shixiong Zhang, Kun Ma, Zhiqin Zhao, Mengnan Li, Yunlong Hou, Yiling Wu.

   Background and aim: Muscular atrophy is one of the most common age-related conditions characterized by the deterioration of skeletal muscle structures and impaired functions. It is associated with cellular senescence and chronic inflammation, which impair the function of muscle stem cells. Bazi Bushen (BZBS) is a patent compound Chinese medicine that has been shown to have anti-aging effects in various animal models. In this study, we investigated the effects and mechanisms of BZBS on muscular atrophy in naturally aged mice.
Experimental procedure: A muscular atrophy model of naturally aged mice (18 months) was employed with administration of BZBS (2 g/kg/d, 1 g/kg/d) and nicotinamide mononucleotide (NMN, 200 mg/kg/d). After six months of drug administration, muscle weight loss, muscle function and muscle histopathology were measured to evaluate the therapeutic effect of BZBS. The expression of cellular senescence, inflammatory and satellite cell-related factors were used to assess the effects of BZBS in inhibiting cellular senescence, reducing inflammation and improving muscle atrophy.
Results and conclusion: Compared with age matched natural aging mice, we found that BZBS improved muscle strength, mass, and morphology by reducing senescent cells, inflammatory cytokines, and intermyofiber fibrosis in aged muscle tissues. We also found that BZBS prevented the reduction of Pax7 positive stem cells and stimulated the activation and differentiation into myocytes. Our results suggest that BZBS might be a promising intervention in senile muscular atrophy.

Keywords:  Bazi Bushen; Cellular senescence; Inflammation; Muscular atrophy; Satellite cell

DOI:  https://doi.org/10.1016/j.jtcme.2024.01.009
Exp Cell Res. 2024 Sep 10. pii: S0014-4827(24)00342-2. [Epub ahead of print] 114251

Impaired Incorporation of Fibronectin into the Extracellular Matrix during Aging Exacerbates the Senescent State of Dermal Cells.

Luce Perié, Cynthia Houël, Anne Zambon, Christelle Guere, Katell Vié, Johanne Leroy-Dudal, Charlotte Vendrely, Rémy Agniel, Franck Carreiras, Cédric R Picot.

  Fibronectin (Fn) is a ubiquitous extracellular matrix (ECM) glycoprotein that acts as an ECM scaffold organizer and is essential in many biological functions, including tissue repair ,differenciation or cancer dissemination. Evidence suggest that amount of Fn change during aging. However, how these changes influence the aging process remains unclear. This study aims to understand Fn influence on cell aging. First, we assess relative level of Fn abundance in both different biopsies skin donors and replicative senescence cellular model. In skin biopsies, we observed that Fn level decreases with aging in the reticular dermis, while its expression remains relatively stable in the papillary dermis, likely to sustain the dermis-epidermis junction. During replicative senescence, in BJ skin fibroblasts, while intracellular Fn increases, we found that secretion and Fn fibrils formation are less effective. Reduced Fn fibrils leads to disorganization of the ECM. This could be explained by the expression of different Fn isoforms observed in the secretome of senescent cells. Surprisingly, the knockdown of Fn delays the onset of senescence while cultivating cells onto a Fn-coated support promotes it. Taken together, these new insights on the role of Fn during aging may emerge new therapeutic strategies on aged-related diseases.

Keywords:  Aging; Fibronectin; extracellular matrix remodeling; senescence; skin

DOI:  https://doi.org/10.1016/j.yexcr.2024.114251
Front Oncol. 2024 ;14 1455492

Metformin and its potential influence on cell fate decision between apoptosis and senescence in cancer, with a special emphasis on glioblastoma.

Melika Hajimohammadebrahim-Ketabforoush, Alireza Zali, Mohammadreza Shahmohammadi, Amir Ali Hamidieh.

  Despite reaching enormous achievements in therapeutic approaches worldwide, GBM still remains the most incurable malignancy among various cancers. It emphasizes the necessity of adjuvant therapies from the perspectives of both patients and healthcare providers. Therefore, most emerging studies have focused on various complementary and adjuvant therapies. Among them, metabolic therapy has received special attention, and metformin has been considered as a treatment in various types of cancer, including GBM. It is clearly evident that reaching efficient approaches without a comprehensive evaluation of the key mechanisms is not possible. Among the studied mechanisms, one of the more challenging ones is the effect of metformin on apoptosis and senescence. Moreover, metformin is well known as an insulin sensitizer. However, if insulin signaling is facilitated in the tumor microenvironment, it may result in tumor growth. Therefore, to partially resolve some paradoxical issues, we conducted a narrative review of related studies to address the following questions as comprehensively as possible: 1) Does the improvement of cellular insulin function resulting from metformin have detrimental or beneficial effects on GBM cells? 2) If these effects are detrimental to GBM cells, which is more important: apoptosis or senescence? 3) What determines the cellular decision between apoptosis and senescence?

Keywords:  AMPK; GBM; P53; apoptosis; calorie restriction; mTOR; metformin; senescence

DOI:  https://doi.org/10.3389/fonc.2024.1455492