bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–03–30
fifteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  2. Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.
  3. Correction to: Biomarkers of cellular senescence and major health outcomes in older adults.
  4. A map of mitochondrial biology reveals the energy landscape of the human brain.
  5. Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
  6. Crosstalk between calcium and reactive oxygen species signaling in cancer revisited.
  7. First map of human brain mitochondria is 'groundbreaking' achievement.
  8. Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart.
  9. Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age.
  10. Ameliorating TIMM50 Loss Slows Senescence by Improving Mitochondrial Structure and Function.
  11. Drugs that target 'zombie' cells soothe an aching back.
  12. Lactylation: A Novel Epigenetic Regulator of Cellular Senescence.
  13. Mito-Modulatory Medication Use and Skeletal Muscle Bioenergetics Among Older Men and Women: the Study of Muscle, Mobility and Aging.
  14. Molecular signatures of cellular senescence in cancer: a critical review of prognostic implications and therapeutic opportunities.
  15. Non-canonical functions of BCL-2 family members in energy metabolism and necrotic cell death regulation.
  1. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  2. Geroscience. 2025 Mar 28.
    Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.
    Sarah Ding, Anisha Banerjee, Sara N Burke, Abbi R Hernandez.
      Many of the "hallmarks of aging" involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation, and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver, and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8 to 25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. Within the brain, SIRT1 and MAPK8 were reduced in CA3 of kTRF-fed rats. Additionally, IGF1 expression was significantly upregulated in the CA1 of cTRF-fed rats, but this effect was ameliorated in the kTRF fed group. AKT and FOXO1 expression were significantly reduced in kTRF-fed rats within liver. Interestingly, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance, and FOXO1 expression was higher in the CA3 of AL-fed rats correlated with the poorest cognitive performance. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.
    Keywords:  Aging; Brain; Diet; Liver; Metabolism; Muscle
    DOI:  https://doi.org/10.1007/s11357-025-01632-7
  3. Geroscience. 2025 Mar 26.
    Correction to: Biomarkers of cellular senescence and major health outcomes in older adults.
    Steven R Cummings, Li-Yung Lui, Zaira Aversa, Theresa Mau, Roger A Fielding, Elizabeth J Atkinson, Sheena Patel, Nathan LeBrasseur.
      
    DOI:  https://doi.org/10.1007/s11357-025-01619-4
  4. Nature. 2025 Mar 26.
    A map of mitochondrial biology reveals the energy landscape of the human brain.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00872-z
  5. J Transl Med. 2025 Mar 24. 23(1): 366
    Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
    Rui Wang, Jie Wang, Jing Yu, Zhiqiang Li, Minfang Zhang, Yuhu Chen, Fen Liu, Dongmei Jiang, Jingfei Guo, Xiaomei Li, Yun Wu.
       BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Recent studies indicate that Mitochondrial fusion protein 2 (Mfn2) maintains intracellular calcium (Ca2+) homeostasis via the mitochondria-associated endoplasmic reticulum membranes (MAMs) pathway, thereby inhibiting PASMCs proliferation and reducing pulmonary artery pressure. However, the precise mechanisms remain unclear.
    METHODS: This study explored the roles of Mfn2 and IP3R3 in PAH progression by assessing their expression in lung tissues of a monocrotaline (MCT)-induced PAH rat model. Immunoprecipitation assays were performed to confirm the interaction between Mfn2 and IP3R3. PASMCs were treated with either silenced or overexpressed Mfn2 and exposed to TNF-ɑ to observe effects on ER stress, IP3R3 expression, mitochondrial Ca2+ transport, and mitochondrial integrity. We also evaluated the effects of 4-phenylbutyric acid (4-PBA) and cistanche phenylethanol glycosides (CPGs) on the Mfn2-IP3R3 interaction in a TNF-α-induced PAH cell model, focusing on Ca2+ transport and mitochondrial structure.
    RESULTS: Mfn2 expression was significantly down-regulated in the MCT-induced PAH rat model. Inhibition of ER stress upregulated Mfn2 expression, downregulated IP3R3 expression, increased mitochondrial Ca2+ concentration, and reduced autophagy, improving pulmonary hemodynamics and vascular remodeling. Overexpression of Mfn2 reduced ER stress, decreased IP3R3 expression, decreased mitochondrial Ca2+ transport, and restored mitochondrial integrity. Immunoprecipitation assays confirmed the interaction between Mfn2 and IP3R3. Inhibition of IP3R3 elevated Mfn2 levels, yielding similar beneficial effects as Mfn2 overexpression. 4-PBA and CPGs modulated the Mfn2-IP3R3 signaling axis, effectively inhibiting PAH progression.
    CONCLUSIONS: Mfn2 mediates mitochondrial Ca2+ transport via IP3R3, suppressing PASMCs proliferation and pulmonary vascular remodeling, underscoring Mfn2's potential in regulating metabolic processes and vascular remodeling in PAH. These findings provide new insights for developing PAH-targeted therapeutics and establish a theoretical basis for traditional Chinese medicine in PAH prevention and treatment.
    Keywords:  Ca2+ homeostasis; Endoplasmic reticulum stress; Mfn2 interact with IP3R3; Mitochondrial autophagy; Pulmonary artery hypertension
    DOI:  https://doi.org/10.1186/s12967-025-06384-8
  6. Cell Calcium. 2025 Mar 18. pii: S0143-4160(25)00023-5. [Epub ahead of print]127 103014
    Crosstalk between calcium and reactive oxygen species signaling in cancer revisited.
    Trayambak Pathak, J Cory Benson, Priscilla W Tang, Mohamed Trebak, Nadine Hempel.
      The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
    Keywords:  Ca(2+); ROS; Redox signaling; cancer
    DOI:  https://doi.org/10.1016/j.ceca.2025.103014
  7. Nature. 2025 Mar 26.
    First map of human brain mitochondria is 'groundbreaking' achievement.
    Nora Bradford.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00848-z
  8. J Cardiovasc Aging. 2025 Jan;pii: 4. [Epub ahead of print]5(1):
    Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart.
    Sakthijothi Muthu, Zinnia Tran, Jayapalraja Thilagavathi, Tanvi Bolarum, Edouard I Azzam, Carolyn K Suzuki, Venkatesh Sundararajan.
       Introduction: Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known.
    Aim: This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging.
    Methods and Results: We utilized 10- and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, Tfam; however, selective mtDNA genes, such as mt-Cytb and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including Lonp1, Yme1l1, Afg3l2, and Spg7, were significantly induced, with a substantial induction of Clpp and Clpx. However, age-associated differences were not observed in the induction of mt chaperones (Hspa9 and Hspd1), but significant induction of Dnaja2, a mitochondrial co-chaperone, was observed. The ER stress transcription factors Xbp1 and Atf6 were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone Hsp90b with no change in Hspa5 and Dnajb9 chaperones. However, induction of Dnm1l was significant, whereas Mfn1 and Fis1 were downregulated in contrast to Mfn2, suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels.
    Conclusion: These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.
    Keywords:  Aging; endoplasmic reticulum stress; heart; mitochondrial stress; oxidative stress
    DOI:  https://doi.org/10.20517/jca.2024.17
  9. JCI Insight. 2025 Mar 25. pii: e183706. [Epub ahead of print]
    Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age.
    Paula M Fraczek, Pamela Duran, Benjamin A Yang, Valeria Ferre, Leanne Alawieh, Jesus A Castor-Macias, Vivian T Wong, Steve D Guzman, Celeste Piotto, Klimentini Itsani, Jacqueline A Larouche, Carlos A Aguilar.
      Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.
    Keywords:  Adult stem cells; Aging; Muscle; Muscle biology; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.183706
  10. Adv Biol (Weinh). 2025 Mar 24. e2400597
    Ameliorating TIMM50 Loss Slows Senescence by Improving Mitochondrial Structure and Function.
    Amrita Nepalia, Deepak Kumar Saini.
      Mitochondrial dysfunction is an irrefutable hallmark of cellular senescence and aging. The dysfunction is marked by increased mitochondrial volume and reduced function, typified by low Adenosine Triphosphate (ATP) production and higher Reactive Oxygen Species (ROS) generation. Over the years, this dysfunction has been linked to Electron Transport Chain (ETC) malfunction and low NAD levels, augmented by poor mitophagy. However, the genetic regulation of mitochondrial dysfunction is still not clear. Here, using several senescence models, the first report on the role of the downregulation of a mitochondrial protein, Translocase of Inner Mitochondrial Membrane 50 (TIMM50), in senescence is presented. The downregulation of TIMM50 is also sufficient for triggering senescence through impaired mitochondrial function, characterized using a variety of mitochondrial function assessment assays. Reduced levels of TIMM50 initiated all the hallmarks of senescence, and overexpression significantly slowed senescence onset in response to an external trigger. The pathway analysis revealed that TIMM50 loss is mediated by the sirtuin1-dependent downregulation of CCAAT enhancer binding protein alpha (CEBPα), a transcription activator for TIMM50 expression. To establish the translational value of the observation, screening several potential anti-aging compounds revealed TIMM50 stabilizing and senescence-delaying effects only for verapamil and mitochondrial ROS quencher, Mito (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO), both known anti-aging entities. Overall, TIMM50 is identified as the key mitochondrial protein whose downregulation is a critical step in initiating cellular senescence.
    Keywords:  TIMM50; aging; cellular senescence; mitochondria; sirtuin
    DOI:  https://doi.org/10.1002/adbi.202400597
  11. Nature. 2025 Mar;639(8056): 841
    Drugs that target 'zombie' cells soothe an aching back.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00770-4
  12. Aging Dis. 2025 Mar 27.
    Lactylation: A Novel Epigenetic Regulator of Cellular Senescence.
    Caiyu Sun, Jiaxuan Li, Lei Dong, Yakui Mou, Bei Zhang, Xicheng Song.
      Cellular senescence is the basic unit of organismal aging, a complicated biological process involving several cell types and tissues. It is also an important mechanism by which the body responds to damage and potential carcinogenesis. However, excessive or abnormal cellular senescence can lead to tissue functional degradation and the occurrence of diseases. In recent years, the role of epigenetic modifications in cellular senescence has received extensive attention. Lactylation, a novel post-translational modification derived from lactate, has recently gained significant attention as a key factor in cellular metabolism and epigenetic regulation, gradually demonstrating its importance in the regulation of cellular senescence. This review emphasizes the bidirectional causal relationship between lactylation and cellular senescence, highlighting its potential as a therapeutic target for aging-related diseases.
    DOI:  https://doi.org/10.14336/AD.2025.0277
  13. J Gerontol A Biol Sci Med Sci. 2025 Mar 23. pii: glaf063. [Epub ahead of print]
    Mito-Modulatory Medication Use and Skeletal Muscle Bioenergetics Among Older Men and Women: the Study of Muscle, Mobility and Aging.
    Howard J Phang, Jaclyn Bergstrom, Rabia S Atayee, Laura A Hart, Peggy M Cawthon, Terri Blackwell, Philip A Kramer, Giovanna Distefano, Erin E Kershaw, Steven R Cummings, Anthony J A Molina.
       BACKGROUND: The potential impacts of drug-induced modulation of mitochondrial function in humans remain unclear despite the high prevalence of "mito-modulatory" medication use among older adults. While these medications, such as statins and metformin, have undergone extensive characterization of their effects on mitochondrial function in vitro, the effects in humans are far more complex and poorly understood.
    METHODS: This study uses data from the Study of Muscle, Mobility and Aging (SOMMA) to evaluate how mito-modulatory medication use is related to skeletal muscle bioenergetic capacity, measured by ex vivo high-resolution respirometry and in vivo phosphorus magnetic resonance spectroscopy in healthy older adults.
    RESULTS: We found that mito-modulatory medication use was related to lower maximal complex I&II supported oxidative phosphorylation (Max OXPHOS), maximal electron transfer system capacity (Max ETS), and maximal ATP production capacity (ATP Max) in men, but not in women. We also found this to be dependent on the number of medications used, in which higher mito-modulatory medication load was associated with lower Max OXPHOS, Max ETS, and ATP Max.
    CONCLUSIONS: Our results provide greater insight into the potential clinical effects of mito-modulatory medication use and highlight the need to test the impact of these medications on mitochondrial function in randomized trials.
    Keywords:  Medicine; Mitochondria; Polypharmacy
    DOI:  https://doi.org/10.1093/gerona/glaf063
  14. Mech Ageing Dev. 2025 Mar 20. pii: S0047-6374(25)00028-4. [Epub ahead of print]225 112052
    Molecular signatures of cellular senescence in cancer: a critical review of prognostic implications and therapeutic opportunities.
    Débora C Santos-Sousa, Solon da Rosa, Eduardo Filippi-Chiela.
      Cellular senescence is a state of permanent loss of proliferative capacity. Therefore, cells that reach a senescent state prevent tumor initiation, acting as an anti-tumor mechanism. However, despite not being proliferative, senescent cells have high secretory activity, constituting the Senescence-Associated Secretory Phenotype (SASP). SASP includes thousands of soluble molecules and extracellular vesicles, through which senescent cells can affect other cells and the extracellular matrix. In advanced tumors, the enrichment of senescent cells can have anti- or pro-tumor effects depending on features like SASP composition, tumor microenvironment (TME) composition, the anatomic site, histopathologic characteristics of malignancy, and tumor molecular background. We reviewed the studies assessing the impact of the senescence status, measured by mRNA or lncRNA molecular signatures, in the prognosis and other clinically relevant information in cancer, including anti-tumor immunity and response to therapy. We discussed the pros and cons of different strategies to define those molecular signatures and the main limitations of the studies. Finally, we also raised clinical challenges regarding the crossroad between cellular senescence and cancer prognosis, including some therapeutic opportunities in the field.
    Keywords:  Cancer; Cellular senescence; Immune system; Molecular signature; Prognosis
    DOI:  https://doi.org/10.1016/j.mad.2025.112052
  15. Cell Cycle. 2025 Mar 27. 1-18
    Non-canonical functions of BCL-2 family members in energy metabolism and necrotic cell death regulation.
    Mohamed El-Mesery, Franziska Rudolf, Yannick Heimann, Georg Häcker, Thomas Brunner.
      The large family of BCL-2 proteins plays a well-established role in the regulation of mitochondrial apoptosis pathway, and the crosstalk between death receptor signaling and mitochondrial apoptosis. Accumulating evidence suggests, however, that various BCL-2 family members are also involved in the regulation of apoptosis-unrelated necrotic forms of cell death, and even non-cell death processes. In this review, we discuss the emerging role of BCL-2 family members, and in particular BIM, in the regulation of mitochondrial dynamics, morphology and energy metabolism, and associated consequences for drug-inuced necrotic cell death.
    Keywords:  BCL-2; apoptosis; electron transport chain; glycolysis; mitochondria; mitotoxicants
    DOI:  https://doi.org/10.1080/15384101.2025.2484868
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