bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–05–26
fourteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications.
  2. Elimination of damaged mitochondria during UVB-induced senescence is orchestrated by NIX-dependent mitophagy.
  3. Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence.
  4. Replication stress as a driver of cellular senescence and aging.
  5. KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
  6. Horizontal mitochondrial transfer as a novel bioenergetic tool for mesenchymal stromal/stem cells: molecular mechanisms and therapeutic potential in a variety of diseases.
  7. Molecular mechanisms of aging and anti-aging strategies.
  8. In Vitro Investigation of Therapy-Induced Senescence and Senescence Escape in Breast Cancer Cells Using Novel Flow Cytometry-Based Methods.
  9. Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
  10. MCU inhibition protects against intestinal ischemia‒reperfusion by inhibiting Drp1-dependent mitochondrial fission.
  11. Mitochondria at the crossroads of health and disease.
  12. Chelating mitochondrial iron and copper: Recipes, pitfalls and promise.
  13. Autophagy and metabolic aging: Current understanding and future applications.
  14. Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.
  1. Cell Calcium. 2024 May 23. pii: S0143-4160(24)00065-4. [Epub ahead of print]121 102907
    Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications.
    Denis Vecellio Reane, Julian D C Serna, Anna Raffaello.
      Calcium (Ca2+) signalling acts a pleiotropic message within the cell that is decoded by the mitochondria through a sophisticated ion channel known as the Mitochondrial Ca2+ Uniporter (MCU) complex. Under physiological conditions, mitochondrial Ca2+ signalling is crucial for coordinating cell activation with energy production. Conversely, in pathological scenarios, it can determine the fine balance between cell survival and death. Over the last decade, significant progress has been made in understanding the molecular bases of mitochondrial Ca2+ signalling. This began with the elucidation of the MCU channel components and extended to the elucidation of the mechanisms that regulate its activity. Additionally, increasing evidence suggests molecular mechanisms allowing tissue-specific modulation of the MCU complex, tailoring channel activity to the specific needs of different tissues or cell types. This review aims to explore the latest evidence elucidating the regulation of the MCU complex, the molecular factors controlling the tissue-specific properties of the channel, and the physiological and pathological implications of mitochondrial Ca2+ signalling in different tissues.
    Keywords:  Brain; Calcium signalling; Heart; Liver; MCU regulation; Mitochondrial calcium uniporter; Skeletal Muscle; tissue-specific modulation
    DOI:  https://doi.org/10.1016/j.ceca.2024.102907
  2. Aging Cell. 2024 May 17. e14186
    Elimination of damaged mitochondria during UVB-induced senescence is orchestrated by NIX-dependent mitophagy.
    Maria Cavinato, Ines Martic, Sophia Wedel, Annabella Pittl, Rafal Koziel, Regina Weinmmüllner, Markus Schosserer, Brigitte Jenewein, Madhusudhan Reddy Bobbili, Elsa Arcalis, Johannes Haybaeck, Gerhard Pierer, Christian Ploner, Martin Hermann, Nikolaus Romani, Matthias Schmuth, Johannes Grillari, Pidder Jansen-Dürr.
      Skin aging is the result of two types of aging, "intrinsic aging" an inevitable consequence of physiologic and genetically determined changes and "extrinsic aging," which is dependent on external factors such as exposure to sunlight, smoking, and dietary habits. UVB causes skin injury through the generation of free radicals and other oxidative byproducts, also contributing to DNA damage. Appearance and accumulation of senescent cells in the skin are considered one of the hallmarks of aging in this tissue. Mitochondria play an important role for the development of cellular senescence, in particular stress-induced senescence of human cells. However, many aspects of mitochondrial physiology relevant to cellular senescence and extrinsic skin aging remain to be unraveled. Here, we demonstrate that mitochondria damaged by UVB irradiation of human dermal fibroblasts (HDF) are eliminated by NIX-dependent mitophagy and that this process is important for cell survival under these conditions. Additionally, UVB-irradiation of human dermal fibroblasts (HDF) induces the shedding of extracellular vesicles (EVs), and this process is significantly enhanced in UVB-irradiated NIX-depleted cells. Our findings establish NIX as the main mitophagy receptor in the process of UVB-induced senescence and suggest the release of EVs as an alternative mechanism of mitochondrial quality control in HDF.
    Keywords:  NIX; UVB; mitochondria; mitophagy; senescence; skin aging; vesicles
    DOI:  https://doi.org/10.1111/acel.14186
  3. Acta Pharmacol Sin. 2024 May 24.
    Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence.
    Ya-Bing Xiong, Wen-Yan Huang, Xian Ling, Shan Zhou, Xiao-Xu Wang, Xiao-Long Li, Li-Li Zhou.
      Renal tubular epithelial cell senescence plays a critical role in promoting and accelerating kidney aging and age-related renal fibrosis. Senescent cells not only lose their self-repair ability, but also can transform into senescence-associated secretory phenotype (SASP) to trigger inflammation and fibrogenesis. Recent studies show that mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, and calcium overload and abnormal calcium-dependent kinase activities are involved in mitochondrial dysfunction-associated senescence. In this study we investigated the role of mitochondrial calcium overload and mitochondrial calcium uniporter (MCU) in kidney aging. By comparing the kidney of 2- and 24-month-old mice, we found calcium overload in renal tubular cells of aged kidney, accompanied by significantly elevated expression of MCU. In human proximal renal tubular cell line HK-2, pretreatment with MCU agonist spermine (10 μM) significantly increased mitochondrial calcium accumulation, and induced the production of reactive oxygen species (ROS), leading to renal tubular cell senescence and age-related kidney fibrosis. On the contrary, pretreatment with MCU antagonist RU360 (10 μM) or calcium chelator BAPTA-AM (10 μM) diminished D-gal-induced ROS generation, restored mitochondrial homeostasis, retarded cell senescence, and protected against kidney aging in HK-2 cells. In a D-gal-induced accelerated aging mice model, administration of BAPTA (100 μg/kg. i.p.) every other day for 8 weeks significantly alleviated renal tubuarl cell senescence and fibrosis. We conclude that MCU plays a key role in promoting renal tubular cell senescence and kidney aging. Targeting inhibition on MCU provides a new insight into the therapeutic strategy against kidney aging.
    Keywords:  calcium overload; kidney aging; mitochondrial calcium uniporter; mitochondrial dysfunction; renal tubular cells
    DOI:  https://doi.org/10.1038/s41401-024-01298-5
  4. Commun Biol. 2024 May 22. 7(1): 616
    Replication stress as a driver of cellular senescence and aging.
    Lauren M Herr, Ethan D Schaffer, Kathleen F Fuchs, Arindam Datta, Robert M Brosh.
      Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying of the genome. While long considered a nexus for DNA damage, the role of replication stress in aging is under-appreciated. The consequential role of replication stress in promotion of organismal aging phenotypes is evidenced by an extensive list of hereditary accelerated aging disorders marked by molecular defects in factors that promote replication fork progression and operate uniquely in the replication stress response. Additionally, recent studies have revealed cellular pathways and phenotypes elicited by replication stress that align with designated hallmarks of aging. Here we review recent advances demonstrating the role of replication stress as an ultimate driver of cellular senescence and aging. We discuss clinical implications of the intriguing links between cellular senescence and aging including application of senotherapeutic approaches in the context of replication stress.
    DOI:  https://doi.org/10.1038/s42003-024-06263-w
  5. J Cell Sci. 2024 May 24. pii: jcs.261728. [Epub ahead of print]
    KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions.
    Peace Atakpa-Adaji, Adelina Ivanova, Karolina Kujawa, Colin W Taylor.
      Inositol 1,4,5-trisphosphate receptors (IP3Rs) are high-conductance channels that allow the regulated redistribution of Ca2+ from the ER to the cytosol and, at specialised membrane contact sites (MCS), to other organelles. Only a subset of IP3Rs release Ca2+ to the cytosol in response to IP3. These 'licensed' IP3Rs are associated with Kras-induced actin-interacting protein (KRAP) beneath the plasma membrane. It is unclear whether KRAP regulates IP3Rs at MCS. We show, using simultaneous measurements of Ca2+ concentration in the cytosol and mitochondrial matrix, that KRAP also licenses IP3Rs to release Ca2+ to mitochondria. Loss of KRAP abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors. KRAP is located at ER-mitochondria membrane contact sites (ERMCS) populated by IP3R clusters. Using a proximity ligation assay between IP3R and voltage-dependent anion channel 1 (VDAC1), we show that loss of KRAP reduces the number of ERMCS. We conclude that KRAP regulates Ca2+ transfer from IP3Rs to mitochondria by both licensing IP3R activity and stabilizing ERMCS.
    Keywords:  Ca2+; Endoplasmic reticulum; HeLa cell; Histamine; IP3 receptor; KRAP; MCU; Membrane contact site; Mitochondria; Proximity ligation assay; VDAC1
    DOI:  https://doi.org/10.1242/jcs.261728
  6. J Transl Med. 2024 May 24. 22(1): 491
    Horizontal mitochondrial transfer as a novel bioenergetic tool for mesenchymal stromal/stem cells: molecular mechanisms and therapeutic potential in a variety of diseases.
    Roberto Iorio, Sabrina Petricca, Vincenzo Mattei, Simona Delle Monache.
      Intercellular mitochondrial transfer (MT) is a newly discovered form of cell-to-cell signalling involving the active incorporation of healthy mitochondria into stressed/injured recipient cells, contributing to the restoration of bioenergetic profile and cell viability, reduction of inflammatory processes and normalisation of calcium dynamics. Recent evidence has shown that MT can occur through multiple cellular structures and mechanisms: tunneling nanotubes (TNTs), via gap junctions (GJs), mediated by extracellular vesicles (EVs) and other mechanisms (cell fusion, mitochondrial extrusion and migrasome-mediated mitocytosis) and in different contexts, such as under physiological (tissue homeostasis and stemness maintenance) and pathological conditions (hypoxia, inflammation and cancer). As Mesenchimal Stromal/ Stem Cells (MSC)-mediated MT has emerged as a critical regulatory and restorative mechanism for cell and tissue regeneration and damage repair in recent years, its potential in stem cell therapy has received increasing attention. In particular, the potential therapeutic role of MSCs has been reported in several articles, suggesting that MSCs can enhance tissue repair after injury via MT and membrane vesicle release. For these reasons, in this review, we will discuss the different mechanisms of MSCs-mediated MT and therapeutic effects on different diseases such as neuronal, ischaemic, vascular and pulmonary diseases. Therefore, understanding the molecular and cellular mechanisms of MT and demonstrating its efficacy could be an important milestone that lays the foundation for future clinical trials.
    Keywords:  Extracellular vesicles; Horizontal mitochondrial transfer; Ischemic vascular diseases; Mesenchymal Stromal/Stem cells; Mitochondria; Neuronal diseases; Tunnelling nanotubes
    DOI:  https://doi.org/10.1186/s12967-024-05047-4
  7. Cell Commun Signal. 2024 May 24. 22(1): 285
    Molecular mechanisms of aging and anti-aging strategies.
    Yumeng Li, Xutong Tian, Juyue Luo, Tongtong Bao, Shujin Wang, Xin Wu.
      Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.
    Keywords:  Aging; Aging triggers; Anti-aging strategies; Senolytic; Synthetic
    DOI:  https://doi.org/10.1186/s12964-024-01663-1
  8. Cells. 2024 May 15. pii: 841. [Epub ahead of print]13(10):
    In Vitro Investigation of Therapy-Induced Senescence and Senescence Escape in Breast Cancer Cells Using Novel Flow Cytometry-Based Methods.
    Fanni Tóth, Zahra Moftakhar, Federica Sotgia, Michael P Lisanti.
      Although cellular senescence was originally defined as an irreversible form of cell cycle arrest, in therapy-induced senescence models, the emergence of proliferative senescence-escaped cancer cells has been reported by several groups, challenging the definition of senescence. Indeed, senescence-escaped cancer cells may contribute to resistance to cancer treatment. Here, to study senescence escape and isolate senescence-escaped cells, we developed novel flow cytometry-based methods using the proliferation marker Ki-67 and CellTrace CFSE live-staining. We investigated the role of a novel senescence marker (DPP4/CD26) and a senolytic drug (azithromycin) on the senescence-escaping ability of MCF-7 and MDA-MB-231 breast cancer cells. Our results show that the expression of DPP4/CD26 is significantly increased in both senescent MCF-7 and MDA-MB-231 cells. While not essential for senescence induction, DPP4/CD26 contributed to promoting senescence escape in MCF-7 cells but not in MDA-MB-231 cells. Our results also confirmed the potential senolytic effect of azithromycin in senescent cancer cells. Importantly, the combination of azithromycin and a DPP4 inhibitor (sitagliptin) demonstrated a synergistic effect in senescent MCF-7 cells and reduced the number of senescence-escaped cells. Although further research is needed, our results and novel methods could contribute to the investigation of the mechanisms of senescence escape and the identification of potential therapeutic targets. Indeed, DPP4/CD26 could be a promising marker and a novel target to potentially decrease senescence escape in cancer.
    Keywords:  breast cancer; flow cytometry; senescence escape; therapy-induced senescence
    DOI:  https://doi.org/10.3390/cells13100841
  9. J Biol Chem. 2024 May 21. pii: S0021-9258(24)01904-5. [Epub ahead of print] 107403
    Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
    Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.
      Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional up-regulated of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally down-regulated in cellular and murine models of mitochondrial defects. We identified a role for the post-transcriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using a model of mitochondria-associated disease in C. elegans, that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107403
  10. Free Radic Biol Med. 2024 May 17. pii: S0891-5849(24)00459-3. [Epub ahead of print]221 111-124
    MCU inhibition protects against intestinal ischemia‒reperfusion by inhibiting Drp1-dependent mitochondrial fission.
    Tulanisa Kadier, Yi-Guo Zhang, Yi-Xin Jing, Zi-Yi Weng, Shi-Shi Liao, Jie Luo, Ke Ding, Chen Cao, Rong Chen, Qing-Tao Meng.
      Intestinal ischemia‒reperfusion (IIR) injury is a common complication of surgery, but clear molecular insights and valuable therapeutic targets are lacking. Mitochondrial calcium overload is an early sign of various diseases and is considered a vital factor in ischemia‒reperfusion injury. The mitochondrial calcium uniporter (MCU), which is located on the inner mitochondrial membrane, is the primary mediator of calcium ion entry into the mitochondria. However, the specific mechanism of MCU in IIR injury remains to be clarified. In this study, we generated an IIR model using C57BL/6 mice and Caco-2 cells and found increases in the calcium levels and MCU expression following IIR injury. The specific inhibition of MCU markedly attenuated IIR injury. Moreover, MCU knockdown alleviates mitochondrial dysfunction by reducing oxidative stress and apoptosis. Mechanistically, MCU knockdown substantially reduced the translocation of Drp1 and thus its binding to Fis1 receptors, resulting in decreased mitochondrial fission. Taken together, our findings demonstrated that MCU is a novel upstream regulator of Drp1 in ischemia‒reperfusion and represents a predictive and therapeutic target for IIR.
    Keywords:  Intestinal ischemia-reperfusion injury; MCU; Mitochondrial calcium overload; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.05.024
  11. Cell. 2024 May 23. pii: S0092-8674(24)00463-X. [Epub ahead of print]187(11): 2601-2627
    Mitochondria at the crossroads of health and disease.
    Anu Suomalainen, Jodi Nunnari.
      Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.
    DOI:  https://doi.org/10.1016/j.cell.2024.04.037
  12. Mitochondrion. 2024 May 20. pii: S1567-7249(24)00061-8. [Epub ahead of print] 101903
    Chelating mitochondrial iron and copper: Recipes, pitfalls and promise.
    Lucie J Lamačová, Jan Trnka.
      Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson's disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism - the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator's intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator-metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation.
    Keywords:  Chelator; Copper; Iron; Mitochondria; Redox cycling; Targeting
    DOI:  https://doi.org/10.1016/j.mito.2024.101903
  13. Biochim Biophys Acta Mol Cell Res. 2024 May 17. pii: S0167-4889(24)00096-X. [Epub ahead of print] 119753
    Autophagy and metabolic aging: Current understanding and future applications.
    Sana Raza.
      "Metabolic aging" refers to the gradual decline in cellular metabolic function across various tissues due to defective hormonal signaling, impaired nutrient sensing, mitochondrial dysfunction, replicative stress, and cellular senescence. While this process usually corresponds with chronological aging, the recent increase in metabolic diseases and cancers occurring at younger ages in humans suggests the premature onset of cellular fatigue and metabolic aging. Autophagy, a cellular housekeeping process facilitated by lysosomes, plays a crucial role in maintaining tissue rejuvenation and health. However, various environmental toxins, hormones, lifestyle changes, and nutrient imbalances can disrupt autophagy in humans. In this review, we explore the connection between autophagy and cellular metabolism, its regulation by extrinsic factors and its modulation to prevent the early onset of metabolic aging.
    Keywords:  Autophagy; Cellular homeostasis; Disease; Metabolic aging; Metabolism
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119753
  14. Am J Physiol Cell Physiol. 2024 May 20.
    Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.
    Sarah E Deemer, Brandon M Roberts, Daniel Larry Smith, Eric P Plaisance, Andy Philp.
      Identifying effective treatment(s) for sarcopenia and sarcopenic obesity are of paramount importance as the global population advances in age and obesity continues to be a worldwide concern. Evidence has shown that a ketogenic diet can be beneficial for preservation of muscle quality and function in older adults, but long-term adherence is low due in part to the high-fat (> 80%), very low carbohydrate (< 5%) composition of the diet. When provided in adequate amounts, exogenous ketone esters can increase circulating ketones to concentrations that exceed those observed during prolonged fasting or starvation without significant alterations in the diet. Ketone esters first emerged in the mid-1990s and their use in pre-clinical and clinical research has escalated within the past 10-15 years. We present findings from a narrative review of the existing literature for a proposed hypothesis on the effects of exogenous ketones as a therapeutic for preservation of skeletal muscle and function within the context of sarcopenic obesity and future directions for exploration. Much of the reviewed literature herein examines the mechanisms of the ketone diester (R, S-1,3-butanediol diacetoacetate) on skeletal muscle mass, muscle protein synthesis, and epigenetic regulation in murine models. Additional studies are needed to further examine the key regulatory factors producing these effects in skeletal muscle, examine convergent and divergent effects among different ketone ester formulations, and establish optimal frequency and dosing regimens to translate these findings into humans.
    Keywords:  aging; ketone diester; ketone monoester; obesity; sarcopenia
    DOI:  https://doi.org/10.1152/ajpcell.00471.2023
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