bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–09–29
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. The role of mitochondria in cytokine and chemokine signalling during ageing.
  2. miR-96-5p expression is sufficient to induce and maintain the senescent cell fate in the absence of stress.
  3. Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
  4. The role of p21 in cellular senescence and aging-related diseases.
  5. Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
  6. Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
  7. S1P regulates intervertebral disc aging by mediating endoplasmic reticulum - mitochondrial calcium ion homeostasis.
  8. The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy.
  9. Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice.
  10. A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
  1. Mech Ageing Dev. 2024 Sep 20. pii: S0047-6374(24)00093-9. [Epub ahead of print]222 111993
    The role of mitochondria in cytokine and chemokine signalling during ageing.
    Maria Kalykaki, Teresa Rubio-Tomás, Nektarios Tavernarakis.
      Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPRmt, in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.
    Keywords:  Age-related disease; Chemokine; Cytokine; Inflammageing; Mitochondrial dysfunction; Senescence
    DOI:  https://doi.org/10.1016/j.mad.2024.111993
  2. Proc Natl Acad Sci U S A. 2024 Oct;121(40): e2321182121
    miR-96-5p expression is sufficient to induce and maintain the senescent cell fate in the absence of stress.
    Fernando E Santiago, Tanvi Adige, Shamsed Mahmud, Xiao Dong, Laura J Niedernhofer, Paul D Robbins.
      Senescence is a cell fate driven by different types of stress that results in exit from the cell cycle and expression of an inflammatory senescence-associated secretory phenotype (SASP). Here, we demonstrate that stable overexpression of miR-96-5p was sufficient to induce cellular senescence in the absence of genotoxic stress, inducing expression of certain markers of early senescence including SASP factors while repressing markers of deep senescence including LINE-1 and type 1 interferons. Stable miR-96-5p overexpression led to genome-wide changes in heterochromatin followed by epigenetic activation of p16Ink4a, p21Cip1, and SASP expression, induction of a marker of DNA damage, and induction of a transcriptional signature similar to other senescent lung and endothelial cell types. Expression of miR-96-5p significantly increased following senescence induction in culture cells and with aging in tissues from naturally aged and Ercc1-/Δ progeroid mice. Mechanistically, miR-96-5p directly suppressed expression of SIN3B and SIN3 corepressor complex constituents KDM5A and MORF4L2, and siRNA-mediated knockdown of these transcriptional regulators recapitulated the senescent phenotype. In addition, pharmacologic inhibition of the SIN3 complex suppressed senescence and SASP markers. These results clearly demonstrate that a single microRNA is sufficient to drive early senescence in the absence of genotoxic stress through targeting epigenetic and transcriptional regulators, identifying novel targets for the development of senotherapeutics.
    Keywords:  SIN3B; aging; epigenetics; miRNA; senescence
    DOI:  https://doi.org/10.1073/pnas.2321182121
  3. Nat Commun. 2024 Sep 27. 15(1): 8274
    Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
    Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.
      A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52183-y
  4. Mol Cells. 2024 Sep 18. pii: S1016-8478(24)00138-9. [Epub ahead of print] 100113
    The role of p21 in cellular senescence and aging-related diseases.
    Jiayu Yan, Siyi Chen, Zimei Yi, Ruowen Zhao, Jiayu Zhu, Shuwen Ding, Junhua Wu.
      During the aging process or disease progression, normal cells and tissues in the body undergo various stresses, leading to cell damage and the need for repair, adaptation, apoptosis, or defense responses. Cellular senescence is a key player in this process, influencing the rate of aging and disease progression. It can be triggered by different stress factors, resulting in irreversible cell cycle arrest and functional decline. Senescent cells often show high expression of cell cycle factors like p21 and p16, which are involved in cell cycle arrest. p16 has long been recognized as a significant marker of aging. Recent evidence suggests that p21high cells and p16high cells represent distinct cell populations in terms of cell type, tissue location, accumulation kinetics, and physiological functions. This article focuses on recent advancements in understanding p21-dependent cellular senescence. It starts by providing an overview of the role of p21 in three primary cellular senescence phenotypes where it plays a crucial role. It then delves into the pathogenesis of diseases closely linked to p21-dependent cellular senescence, particularly metabolic disorders and cardiovascular diseases. The article also discusses progress in p21-related animal models and outlines strategies for utilizing p21 to intervene in cellular senescence by delaying aging, eliminating senescent cells, and rejuvenating senescent cells. This review systematically examines the pathogenesis of p21-dependent cellular senescence, emphasizing its importance in studying aging heterogeneity and developing new senolytic therapies. It aims to stimulate future research on leveraging p21 to enhance the characteristics of senescent cells, allowing more precise methods for eliminating harmful senescent cells at the right time, thereby delaying aging and potentially achieving rejuvenation.
    Keywords:  aging-related diseases; cellular senescence; p21; senolytic; senomorphic
    DOI:  https://doi.org/10.1016/j.mocell.2024.100113
  5. Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]
    Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
    N Moradi, V C Sanfrancesco, S Champsi, D A Hood.
      Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.028
  6. FEBS J. 2024 Sep 26.
    Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
    Phineas Smith, Bernadette Carroll.
      Ageing is defined as the progressive loss of tissue function and regenerative capacity and is caused by both intrinsic factors i.e. the natural accumulation of damage, and extrinsic factors i.e. damage from environmental stressors. Cellular senescence, in brief, is an irreversible exit from the cell cycle that occurs primarily in response to excessive cellular damage, such as from ultraviolet (UV) exposure and oxidative stress, and it has been comprehensively demonstrated to contribute to tissue and organismal ageing. In this review, we will focus on the skin, an organ which acts as an essential protective barrier against injury, insults, and infection. We will explore the evidence for the existence and contribution of cellular senescence to skin ageing. We discuss the known molecular mechanisms driving senescence in the skin, with a focus on the dysregulation of the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1). We explore the interplay of dysregulated mTORC1 with lysosomes and how they contribute to senescence phenotypes.
    Keywords:  ageing; lysosome; mTORC1; senescence; skin
    DOI:  https://doi.org/10.1111/febs.17281
  7. JCI Insight. 2024 Sep 24. pii: e177789. [Epub ahead of print]
    S1P regulates intervertebral disc aging by mediating endoplasmic reticulum - mitochondrial calcium ion homeostasis.
    Bingjie Zheng, Xuyang Zhang, Xiangxi Kong, Jie Li, Bao Huang, Hui Li, Zhongyin Ji, Xiaoan Wei, Siyue Tao, Zhi Shan, Zemin Ling, Junhui Liu, Jian Chen, Fengdong Zhao.
      Mechanistically, S1P deficiency impeded COP II-mediated transport vesicles formation, which leads to proteins retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow, resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.
    Keywords:  Aging; Bone biology; Bone disease
    DOI:  https://doi.org/10.1172/jci.insight.177789
  8. Cancer Metastasis Rev. 2024 Sep 23.
    The role of mitochondria in tumor metastasis and advances in mitochondria-targeted cancer therapy.
    Fanglu Chen, Yucheng Xue, Wenkan Zhang, Hao Zhou, Zhiyi Zhou, Tao Chen, Eloy YinWang, Hengyuan Li, Zhaoming Ye, Junjie Gao, Shengdong Wang.
      Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies.
    Keywords:  Immunotherapy; Metabolism; Mitochondria transfer; Mitochondrial genetics; Mitophagy; Tumor metastasis
    DOI:  https://doi.org/10.1007/s10555-024-10211-9
  9. Theranostics. 2024 ;14(14): 5429-5442
    Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice.
    Priyadarshani Nadeeshika Samarawickrama, Guiqin Zhang, Enfang Zhu, Xin Dong, Ayesha Nisar, Hong Zhu, Yuan Ma, Zheyan Zhou, Honglin Yang, Li Gui, Mei Cao, Wei Li, Yu Chang, Meiting Zi, Haoling Cui, Zhongping Duan, Xuan Zhang, Wen Li, Yonghan He.
      Background: Diabetic foot ulcers (DFUs) pose a substantial healthcare challenge due to their high rates of morbidity, recurrence, disability, and mortality. Current DFU therapeutics continue to grapple with multiple limitations. Senescent cells (SnCs) have been found to have a beneficial effect on acute wound healing, however, their roles in chronic wounds, such as DFU, remain unclear. Methods and results: We collected skin, fat, and muscle samples from clinical patients with DFU and lower limb fractures. RNA-sequencing combined with qPCR analyses on these samples demonstrate a significant accumulation of SnCs at DFU, as indicated by higher senescence markers (e.g., p16 and p21) and a senescence-associated secretory phenotype (SASP). We constructed a type 2 diabetic model of db/db mice, fed with a high-fat diet (Db-HFD), which were wounded using a 6 mm punch to the dorsal skin. HFD slightly affected wound healing in wild-type (WT) mice, but high glucose significantly delayed wound healing in the Db-HFD mice. We injected the mice with a previously developed fluorescent probe (XZ1208), which allows the detection of SnCs in vivo, and observed a strong senescence signal at the wound site of the Db-HFD mice. Contrary to the beneficial effects of SnCs in acute wound healing, our results demonstrated that clearance of SnCs using the senolytic compound ABT263 significantly accelerated wound healing in Db-HFD mice. Conclusion: Collectively, these findings suggest that SnCs critically accumulate at wound sites, delaying the healing process in DFUs. Thus, targeting SnCs with senolytic therapy represents a promising approach for DFU treatment, potentially improving the quality of life for patients with DFUs.
    Keywords:  cellular senescence; diabetic foot ulcer; imaging; senolytic; wound healing
    DOI:  https://doi.org/10.7150/thno.100991
  10. Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]
    A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.
    Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt
    DOI:  https://doi.org/10.1016/j.cell.2024.08.045
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