bims-cesemi 2024-06-30 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024‒06‒30
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor

Targeting metabolism to influence cellular senescence a promising anti-cancer therapeutic strategy.
Quercetin Induces Senolysis of Doxorubicin-Induced Senescent Fibroblasts by Reducing Autophagy, Preventing Their Pro-tumour Effect on Osteosarcoma Cells.
Moderate-Intensity Exercise Enhances Mitochondrial Biogenesis Markers in the Skeletal Muscle of a Mouse Model Affected by Diet-Induced Obesity.
PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.
SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential therapeutic targets.
Neuronal senescence may drive brain aging.
Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.
Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.
MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling.
FRMD6 determines the cell fate towards senescence: involvement of the Hippo-YAP-CCN3 axis.
Calcium Regulation of Connexin Hemichannels.
The extracellular matrix integrates mitochondrial homeostasis.

Biomed Pharmacother. 2024 Jun 25. pii: S0753-3322(24)00846-1. [Epub ahead of print]177 116962

Targeting metabolism to influence cellular senescence a promising anti-cancer therapeutic strategy.

Zehua Wang, Jianwen Gao, Congjian Xu.

  Metabolic disorders are considered the hallmarks of cancer and metabolic reprogramming is emerging as a new strategy for cancer treatment. Exogenous and endogenous stressors can induce cellular senescence; the interactions between cellular senescence and systemic metabolism are dynamic. Cellular senescence disrupts metabolic homeostasis in various tissues, which further promotes senescence, creating a vicious cycle facilitating tumor occurrence, recurrence, and altered outcomes of anticancer treatments. Therefore, the regulation of cellular senescence and related secretory phenotypes is considered a breakthrough in cancer therapy; moreover, proteins involved in the associated pathways are prospective therapeutic targets. Although studies on the association between cellular senescence and tumors have emerged in recent years, further elucidation of this complex correlation is required for comprehensive knowledge. In this paper, we review the research progress on the correlation between cell aging and metabolism, focusing on the strategies of targeting metabolism to modulate cellular senescence and the progress of relevant research in the context of anti-tumor therapy. Finally, we discuss the significance of improving the specificity and safety of anti-senescence drugs, which is a potential challenge in cancer therapy.

Keywords:  Aging; Anti-cancer treatment; Metabolic reprogramming; Senescence; Senolytic

DOI:  https://doi.org/10.1016/j.biopha.2024.116962
Mech Ageing Dev. 2024 Jun 21. pii: S0047-6374(24)00057-5. [Epub ahead of print] 111957

Quercetin Induces Senolysis of Doxorubicin-Induced Senescent Fibroblasts by Reducing Autophagy, Preventing Their Pro-tumour Effect on Osteosarcoma Cells.

Elisa Bientinesi, Sara Ristori, Matteo Lulli, Daniela Monti.

  Cellular senescence contributes to ageing and age-related diseases, and multiple therapeutic strategies are being developed to counteract it. Senolytic drugs are being tested in clinical trials to eliminate senescent cells selectively, but their effects and mechanisms are still unclear. Several studies reveal that the upregulation of senescence-associated secretory phenotype (SASP) factors in senescent cells is accompanied by increased autophagic activity to counteract the endoplasmic reticulum (ER) stress. Our study shows that Doxo-induced senescent fibroblasts yield several SASP factors and exhibit increased autophagy. Interestingly, Quercetin, a bioactive flavonoid, reduces autophagy, increases ER stress, and partially triggers senescent fibroblast death. Given the role of senescent cells in cancer progression, we tested the effect of conditioned media from untreated and quercetin-treated senescent fibroblasts on osteosarcoma cells to determine whether senolytic treatment affected tumour cell behaviour. We report that the partial senescent fibroblast clearance, achieved by quercetin, reduced osteosarcoma cell invasiveness, curbing the pro-tumour effects of senescent cells. The reduction of cell autophagic activity and increased ER stress, an undescribed effect of quercetin, emerges as a new vulnerability of Doxo-induced senescent fibroblasts and may provide a potential therapeutic target for cancer treatment and suggest novel drug combinations as a promising strategy against the tumour.

Keywords:  Autophagy; Cancer; Endoplasmic reticulum stress; Quercetin; Senolysis

DOI:  https://doi.org/10.1016/j.mad.2024.111957
Nutrients. 2024 Jun 12. pii: 1836. [Epub ahead of print]16(12):

Moderate-Intensity Exercise Enhances Mitochondrial Biogenesis Markers in the Skeletal Muscle of a Mouse Model Affected by Diet-Induced Obesity.

Lauren Jun, Emily Knight, Tom L Broderick, Layla Al-Nakkash, Brielle Tobin, Thangiah Geetha, Jeganathan Ramesh Babu.

  Skeletal muscle is composed of bundles of muscle fibers with distinctive characteristics. Oxidative muscle fiber types contain higher mitochondrial content, relying primarily on oxidative phosphorylation for ATP generation. Notably, as a result of obesity, or following prolonged exposure to a high-fat diet, skeletal muscle undergoes a shift in fiber type toward a glycolytic type. Mitochondria are highly dynamic organelles, constantly undergoing mitochondrial biogenesis and dynamic processes. Our study aims to explore the impact of obesity on skeletal muscle mitochondrial biogenesis and dynamics and also ascertain whether the skeletal muscle fiber type shift occurs from the aberrant mitochondrial machinery. Furthermore, we investigated the impact of exercise in preserving the oxidative muscle fiber types despite obesity. Mice were subjected to a normal standard chow and water or high-fat diet with sugar water (HFS) with or without exercise training. After 12 weeks of treatment, the HFS diet resulted in a noteworthy reduction in the markers of mitochondrial content, which was recovered by exercise training. Furthermore, higher mitochondrial biogenesis markers were observed in the exercised group with a subsequent increase in the mitochondrial fission marker. In conclusion, these findings imply a beneficial impact of moderate-intensity exercise on the preservation of oxidative capacity in the muscle of obese mouse models.

Keywords:  exercise; high-fat diet; mitochondria; obesity; skeletal muscle

DOI:  https://doi.org/10.3390/nu16121836
Autophagy. 2024 Jun 26. 1-16

PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting.

Qingyuan Zhang, Chunhui Chen, Ye Ma, Xinyi Yan, Nianhong Lai, Hao Wang, Baogui Gao, Anna Meilin Gu, Qinrui Han, Qingling Zhang, Lei La, Xuegang Sun.

  Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.

Keywords:  AGER; S100A9; cachexia; cancer; mitophagy; muscle atrophy

DOI:  https://doi.org/10.1080/15548627.2024.2360340
Biomed Pharmacother. 2024 Jun 21. pii: S0753-3322(24)00801-1. [Epub ahead of print]177 116917

SIRT1 signaling pathways in sarcopenia: Novel mechanisms and potential therapeutic targets.

Luning Yang, Di Liu, Shide Jiang, Hengzhen Li, Lin Chen, Yuxiang Wu, Anko Elijah Essien, Michael Opoku, Shinen Naranmandakh, ShuGuang Liu, Qin Ru, Yusheng Li.

  Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of the elderly population. Sirtuin 1 (SIRT1), as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in various aging-related signaling pathways and exert protective effect on many human diseases. SIRT1 functioned as an important role in the occurrence and progression of sarcopenia through regulating key pathways related to protein homeostasis, apoptosis, mitochondrial dysfunction, insulin resistance and autophagy in skeletal muscle, including SIRT1/Forkhead Box O (FoxO), AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor κB (NF-κB), SIRT1/p53, AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and SIRT1/live kinase B1 (LKB1)/AMPK pathways. However, the specific mechanisms of these processes have not been fully illuminated. Currently, several SIRT1-mediated interventions on sarcopenia have been preliminarily developed, such as SIRT1 activator polyphenolic compounds, exercising and calorie restriction. In this review, we summarized the predominant mechanisms of SIRT1 involved in sarcopenia and therapeutic modalities targeting the SIRT1 signaling pathways for the prevention and prognosis of sarcopenia.

Keywords:  Aging; Prevention; Sarcopenia; Sirtuin 1

DOI:  https://doi.org/10.1016/j.biopha.2024.116917
Science. 2024 Jun 28. 384(6703): 1404-1406

Neuronal senescence may drive brain aging.

Joseph R Herdy, Jerome Mertens, Fred H Gage.

Senescence of postmitotic neurons presents challenges and opportunities to modify brain aging.

DOI: https://doi.org/10.1126/science.adi3450
Adv Biol (Weinh). 2024 Jun 27. e2400079

Biomarkers of Cellular Senescence and Aging: Current State-of-the-Art, Challenges and Future Perspectives.

Subramanian Muthamil, Hyun-Yong Kim, Hyun-Jun Jang, Ji-Hyo Lyu, Ung Cheol Shin, Younghoon Go, Seong-Hoon Park, Hee Gu Lee, Jun Hong Park.

  Population aging has increased the global prevalence of aging-related diseases, including cancer, sarcopenia, neurological disease, arthritis, and heart disease. Understanding aging, a fundamental biological process, has led to breakthroughs in several fields. Cellular senescence, evinced by flattened cell bodies, vacuole formation, and cytoplasmic granules, ubiquitously plays crucial roles in tissue remodeling, embryogenesis, and wound repair as well as in cancer therapy and aging. The lack of universal biomarkers for detecting and quantifying senescent cells, in vitro and in vivo, constitutes a major limitation. The applications and limitations of major senescence biomarkers, including senescence-associated β-galactosidase staining, telomere shortening, cell-cycle arrest, DNA methylation, and senescence-associated secreted phenotypes are discussed. Furthermore, explore senotherapeutic approaches for aging-associated diseases and cancer. In addition to the conventional biomarkers, this review highlighted the in vitro, in vivo, and disease models used for aging studies. Further, technologies from the current decade including multi-omics and computational methods used in the fields of senescence and aging are also discussed in this review. Understanding aging-associated biological processes by using cellular senescence biomarkers can enable therapeutic innovation and interventions to improve the quality of life of older adults.

Keywords:  SASPs; SA‐β‐gal; aging; multi‐omics; organoids; senescence; senotherapeutics

DOI:  https://doi.org/10.1002/adbi.202400079
Sci Adv. 2024 Jun 28. 10(26): eadn4508

Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle.

Lingling Zhang, Chenhao Xin, Shuo Wang, Shixuan Zhuo, Jing Zhu, Zi Li, Yuyi Liu, Lifeng Yang, Yan Chen.

Once considered as a "metabolic waste," lactate is now recognized as a major fuel for tricarboxylic acid (TCA) cycle. Our metabolic flux analysis reveals that skeletal muscle mainly uses lactate to fuel TCA cycle. Lactate is transported through the cell membrane via monocarboxylate transporters (MCTs) in which MCT1 is highly expressed in the muscle. We analyzed how MCT1 affects muscle functions using mice with specific deletion of MCT1 in skeletal muscle. MCT1 deletion enhances running performance, increases oxidative fibers while decreasing glycolytic fibers, and enhances flux of glucose to TCA cycle. MCT1 deficiency increases the expression of mitochondrial proteins, augments cell respiration rate, and elevates mitochondrial activity in the muscle. Mechanistically, the protein level of PGC-1α, a master regulator of mitochondrial biogenesis, is elevated upon loss of MCT1 via increases in cellular NAD+ level and SIRT1 activity. Collectively, these results demonstrate that MCT1-mediated lactate shuttle plays a key role in regulating muscle functions by modulating mitochondrial biogenesis and TCA flux.

DOI: https://doi.org/10.1126/sciadv.adn4508
Nat Commun. 2024 Jun 26. 15(1): 5423

MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling.

Hervé Técher, Diyavarshini Gopaul, Jonathan Heuzé, Nail Bouzalmad, Baptiste Leray, Audrey Vernet, Clément Mettling, Jérôme Moreaux, Philippe Pasero, Yea-Lih Lin.

Oncogene-induced senescence (OIS) arrests cell proliferation in response to replication stress (RS) induced by oncogenes. OIS depends on the DNA damage response (DDR), but also on the cGAS-STING pathway, which detects cytosolic DNA and induces type I interferons (IFNs). Whether and how RS and IFN responses cooperate to promote OIS remains unknown. Here, we show that the induction of OIS by the H-RASV12 oncogene in immortalized human fibroblasts depends on the MRE11 nuclease. Indeed, treatment with the MRE11 inhibitor Mirin prevented RS, micronuclei formation and IFN response induced by RASV12. Overexpression of the cytosolic nuclease TREX1 also prevented OIS. Conversely, overexpression of a dominant negative mutant of TREX1 or treatment with IFN-β was sufficient to induce RS and DNA damage, independent of RASV12 induction. These data suggest that the IFN response acts as a positive feedback loop to amplify DDR in OIS through a process regulated by MRE11 and TREX1.

DOI: https://doi.org/10.1038/s41467-024-49740-w
Cell Death Differ. 2024 Jun 26.

FRMD6 determines the cell fate towards senescence: involvement of the Hippo-YAP-CCN3 axis.

Jung-Jin Park, Su Jin Lee, Minwoo Baek, Ok-Jun Lee, Seungyoon Nam, Jaehong Kim, Jin Young Kim, Eun-Young Shin, Eung-Gook Kim.

Cellular senescence, a hallmark of aging, is pathogenically linked to the development of aging-related diseases. This study demonstrates that FRMD6, an upstream component of the Hippo/YAP signaling cascade, is a key regulator of senescence. Proteomic analysis revealed that FRMD6 is upregulated in senescent IMR90 fibroblasts under various senescence-inducing conditions. Silencing FRMD6 mitigated the senescence of IMR90 cells, suggesting its requirement in senescence. Conversely, the overexpression of FRMD6 alone induced senescence in cells and in lung tissue, establishing a causal link. The elevated FRMD6 levels correlated well with increased levels of the inhibitory phosphorylated YAP/TAZ. We identified cellular communication network factor 3 (CCN3), a key component of the senescence-associated secretory phenotype regulated by YAP, whose administration attenuated FRMD6-induced senescence in a dose-dependent manner. Mechanistically, FRMD6 interacted with and activated MST kinase, which led to YAP/TAZ inactivation. The expression of FRMD6 was regulated by the p53 and SMAD transcription factors in senescent cells. Accordingly, the expression of FRMD6 was upregulated by TGF-β treatment that activates those transcription factors. In TGF-β-treated IMR90 cells, FRMD6 mainly segregated with p21, a senescence marker, but rarely segregated with α-SMA, a myofibroblast marker, which suggests that FRMD6 has a role in directing cells towards senescence. Similarly, in TGF-β-enriched environments, such as fibroblastic foci (FF) from patients with idiopathic pulmonary fibrosis, FRMD6 co-localized with p16 in FF lining cells, while it was rarely detected in α-SMA-positive myofibroblasts that are abundant in FF. In sum, this study identifies FRMD6 as a novel regulator of senescence and elucidates the contribution of the FRMD6-Hippo/YAP-CCN3 axis to senescence.

DOI: https://doi.org/10.1038/s41418-024-01333-2
Int J Mol Sci. 2024 Jun 15. pii: 6594. [Epub ahead of print]25(12):

Calcium Regulation of Connexin Hemichannels.

Erva Bayraktar, Diego Lopez-Pigozzi, Mario Bortolozzi.

  Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions, HCs can form gap junction (GJ) channels, providing a direct diffusive path between neighbouring cells. In addition, unpaired HCs provide conduits for the exchange of solutes between the cytoplasm and the extracellular milieu, including messenger molecules involved in paracrine signalling. The synergistic action of membrane potential and Ca2+ ions controls the gating of the large and relatively unselective pore of connexin HCs. The four orders of magnitude difference in gating sensitivity to the extracellular ([Ca2+]e) and the cytosolic ([Ca2+]c) Ca2+ concentrations suggests that at least two different Ca2+ sensors may exist. While [Ca2+]e acts as a spatial modulator of the HC opening, which is most likely dependent on the cell layer, compartment, and organ, [Ca2+]c triggers HC opening and the release of extracellular bursts of messenger molecules. Such molecules include ATP, cAMP, glutamate, NAD+, glutathione, D-serine, and prostaglandins. Lost or abnormal HC regulation by Ca2+ has been associated with several diseases, including deafness, keratitis ichthyosis, palmoplantar keratoderma, Charcot-Marie-Tooth neuropathy, oculodentodigital dysplasia, and congenital cataracts. The fact that both an increased and a decreased Ca2+ sensitivity has been linked to pathological conditions suggests that Ca2+ in healthy cells finely tunes the normal HC function. Overall, further investigation is needed to clarify the structural and chemical modifications of connexin HCs during [Ca2+]e and [Ca2+]c variations. A molecular model that accounts for changes in both Ca2+ and the transmembrane voltage will undoubtedly enhance our interpretation of the experimental results and pave the way for developing therapeutic compounds targeting specific HC dysfunctions.

Keywords:  ATP release; HC dysfunction; calcium; connexin; connexon; extracellular and intracellular gating; gap junction; hemichannel; paracrine signalling; pathological mutations; sensitivity to Ca2+; voltage

DOI:  https://doi.org/10.3390/ijms25126594
Cell. 2024 Jun 24. pii: S0092-8674(24)00638-X. [Epub ahead of print]

The extracellular matrix integrates mitochondrial homeostasis.

Hanlin Zhang, C Kimberly Tsui, Gilberto Garcia, Larry K Joe, Haolun Wu, Ayane Maruichi, Wudi Fan, Sentibel Pandovski, Peter H Yoon, Brant M Webster, Jenni Durieux, Phillip A Frankino, Ryo Higuchi-Sanabria, Andrew Dillin.

  Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.

Keywords:  TGF-β; TMEM2; extracellular matrix; hyaluronan; immunity; mitochondria

DOI:  https://doi.org/10.1016/j.cell.2024.05.057