bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–06–15
fourteen papers selected by
Julio Cesar Cardenas, Universidad Mayor



  1. Biochim Biophys Acta Mol Cell Res. 2025 Jun 06. pii: S0167-4889(25)00103-X. [Epub ahead of print] 119998
      The presenilin-associated rhomboid-like protein (PARL) is a mitochondrial inner membrane serine protease that is a key regulator of several cellular processes, including apoptosis, metabolism, inflammation and stress responses. While recent studies suggest that PARL may play a role in mitochondrial calcium homeostasis, the underlying mechanisms remain poorly understood. In this study, we investigated the effects of PARL modulation on mitochondrial and cytosolic calcium dynamics, as well as mitochondrial membrane potential. Our results show that altering PARL protein levels, through both overexpression and silencing, significantly affects mitochondrial calcium uptake, without influencing cytosolic calcium transients or mitochondrial membrane potential. Despite the observed changes in mitochondrial calcium dynamics, PARL does not interact with the mitochondrial calcium uniporter complex (mtCU) regulators MICU1 and MICU2, which are critical for regulating mitochondrial calcium influx. However, we observed alterations in the protein levels of MICU1 and MICU2, either in their monomeric or dimeric forms, suggesting that PARL may influence these mtCU components indirectly. Interestingly, the pore-forming subunit MCU, and the structural subunit EMRE, essential for the assembly of the mtCU, were unaffected by PARL modulation. These findings suggest that the role of PARL in modulating mitochondrial calcium homeostasis may involve indirect mechanisms, potentially involving other regulatory pathways. Overall, our study provides novel insights into the functional role of PARL in mitochondrial calcium regulation, offering potential avenues for further investigation into its broader cellular functions.
    Keywords:  Calcium signaling; Mitochondria; Mitochondrial calcium uniporter; Mitochondrial intermembrane proteolysis; PARL; Rhomboid protease
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119998
  2. Nature. 2025 Jun 11.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01583-1
  3. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2506321122
      Cellular senescence, a major contributor to aging and age-related pathologies, is characterized by irreversible proliferative arrest and a disease-linked, proinflammatory profile known as the Senescence Associated Secretory Phenotype (SASP). A critical unanswered question is whether these properties are regulated by specific enhancer subsets, potentially licensing strategies that selectively block deleterious SASP components. Here, we identify two functionally distinct and independently regulated enhancer programs underlying senescence that are controlled by different TGF-β family ligands. Whereas Activin A stimulates recruitment of nuclear factor IA/C (NFIA/C) and SMAD2/3 transcription factors to an enhancer network that induces proliferation arrest, TGF-β2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving the SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-β2 (TGFB2) and Activin A (INHBA) transcription units, both of which are significantly up-regulated in replicative senescence. The characteristic enhancer usage and transcriptional landscape of high-passage senescent cells are sensitive to rapamycin treatment, discontinuation of which results in robust but selective senescent enhancer activation and exacerbation of the SASP. Collectively, this study uncovers separable enhancer programs and their key constituent transcription factors that contribute to the canonical features of cellular senescence, potentially informing the development of SASP-targeted therapies.
    Keywords:  NFI; SMAD2/3; cellular senescence; enhancers; p65
    DOI:  https://doi.org/10.1073/pnas.2506321122
  4. Nature. 2025 Jun 11.
      Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-025-09097-6
  5. Cell Reprogram. 2025 Jun 09.
      Sahu et al. (2024) demonstrate that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells rejuvenates senescent cells while maintaining cellular identity. In a progeroid and naturally aged mouse model, a single AAV injection improved lifespan, reduced inflammation, restored tissue integrity, and enhanced wound healing. Complementary results in human fibroblasts confirmed Cdkn2a-driven OSK expression attenuated inflammation-associated genes during replicative senescence and treatments inducing DNA damage. These encouraging results highlight its potential as a safer alternative to systemic senolytic therapies for age-associated disorders.
    Keywords:  Hutchinson-Gilford progeria syndrome; aging; partial reprogramming; senescent cells
    DOI:  https://doi.org/10.1089/cell.2025.0018
  6. Front Physiol. 2025 ;16 1596636
      Pyruvate dehydrogenase phosphatase (PDP), a structurally conserved member of the protein phosphatase C family (PP2C) of proteins, is a key regulatory enzyme responsible for reactivation of the mitochondrial gate-keeper, pyruvate dehydrogenase (PDH). Tissue-specific expression of PDP isozymes, specifically PDP1 and PDP2 facilitate regulation of the multi-subunit PDH, influencing flux of substrates to the TCA cycle. PDP1 is a heterodimeric, Ca2+ sensitive isoform, predominantly expressed in muscle tissue where its role in regulating PDH activity is well established. Emerging research suggests that it is involved in various diseases, including pancreatic ductal adenocarcinoma, cardiomyogenesis defects, traumatic brain injury, and Barth syndrome. In this review, we discuss recent studies revealing the crucial role of PDP1 and its dysregulation in various metabolic disorders, thereby highlighting its potential as a therapeutic target for these debilitating diseases.
    Keywords:  barth syndrome; cancer; cardiomyogenesis; pyruvate dehydrogenase complex; pyruvate dehydrogenase phosphatase 1; traumatic brain injury
    DOI:  https://doi.org/10.3389/fphys.2025.1596636
  7. Geroscience. 2025 Jun 12.
      Skeletal muscle is a primary tissue of dysfunction during both aging and obesity. Recently, the coincidence of obesity and aging has gained attention due to the intersection of the obesity epidemic with an aging demographic. Both aging and obesity are associated with marked defects in skeletal muscle metabolic health. Despite these findings, we have a poor understanding of how obesity and aging may interact to impact skeletal muscle mass and metabolic health. Therefore, we investigated the impact of high-fat diet (HFD)-induced obesity on skeletal muscle mass, mitochondrial function, transcriptomics, and whole-body metabolism in young and aged mice. We observed main effects of diet and age on several measures of whole-body metabolic function (VO2, VCO2, and RER). Complex I-driven mitochondrial proton leak was significantly elevated by HFD-induced obesity across both age groups; however, a main effect of aging for reduced complex I leak was detected in the soleus muscle. Interestingly, aged animals fed a HFD did not exhibit lower muscle mass than chow-fed young animals, but did present with stark increases in muscle triglyceride content and a unique transcriptional response to HFD. HFD-induced obesity impacted the muscle transcriptome differently in the muscles of young and aged mice, indicating that obesity can change altered gene expression with age. Our findings suggest that the presence of obesity can both compound and counteract age-associated changes to muscle mass, gene expression, and mitochondrial function.
    Keywords:  Aging; Metabolism; Mitochondria; Obesity; Sarcopenic obesity; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11357-025-01726-2
  8. Acta Pharmacol Sin. 2025 Jun 11.
      Temozolomide (TMZ) is an alkylating agent recommended as the first-line pharmaceutical for glioblastoma (GBM), but its efficacy is limited by the development of acquired resistance in GBM cells. TMZ resistance is regulated by multiple factors such as MGMT upregulation and metabolism reprogramming, its underlying mechanism still remains elusive. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor regulating the metabolism of lipid and glucose, while histone 3 lactylation at lysine on position 18 (H3K18la) could promote cancer cells' resistance to therapeutic drugs. In this study we investigated the role of PPARα in regulating H3K18la and TMZ sensitivity in glioblastoma (GBM) cells. We established TMZ-resistant U87TR, U251TR, and U118TR cells by treating the parental U87, U251, and U118 cells with increased dosages of TMZ until the cells could resist TMZ (200 μM). We found that in TMZ-resistant cells, H3K18la level was apparently upregulated accompanied by increased ECAR (extracellular acidification rate) and intracellular lactate levels, whereas lactate (20 mM) time-dependently upregulated H3K18la in U87 and U251 cells. We found that PPARα was activated by TMZ in U87, U251, and U118 cells, but was inactivated when the cells became resistant to TMZ. In TMZ-sensitive glioma cells, TMZ triggered PPARα activation by causing DNA DSBs-dependent p38 MAPK activation. The activated PPARα upregulated its downstream signal ACOX1, which not only inhibited lactate-mediated H3K18 lactylation by promoting ROS-dependent PKM2 downregulation, but also reversely enhanced PPARα activation through ROS-activated ASK1/p38 MAPK pathway. In GBM cells resistant to TMZ, PPARα and p38 MAPK were both inactivated, but H3K18 lactylation was obviously upregulated. Targeting activation of PPARα with gemfibrozil or GW7647 not only sensitized GBM cells to TMZ but also effectively reversed the acquired resistance of GBM cells to TMZ by suppression of H3K18 lactylation through upregulation of ACOX1. Taken together, PPARα contributed to TMZ-induced growth arrest in GBM cells by inhibiting lactate-mediated H3K18 lactylation, targeting activation of PPARα may be a new strategy to improve the treatment effect of TMZ against GBM.
    Keywords:  ACOX1; H3K18 lactylation; PKM2; PPARα; glioblastoma; temozolomide resistance
    DOI:  https://doi.org/10.1038/s41401-025-01600-z
  9. Redox Biol. 2025 Jun 06. pii: S2213-2317(25)00229-0. [Epub ahead of print]85 103716
      Dry age-related macular degeneration (AMD) is one of the common blinding eye diseases, with pathological hallmarks of lipofuscin accumulation, neuroretina atrophy and retinal pigment epithelium (RPE) degeneration. Currently, there are no effective interventions for dry AMD. Although there is already evidence suggesting a link between cellular senescence and age-related diseases, it is still unclear whether long-term senolytic therapy with Dasatinib and Quercetin (D + Q) can slow the progression of dry AMD and ultimately prevent retinal structural damage and function loss. Mice lacking the Abca4 and Rdh8 genes (Abca4-/-Rdh8-/- mice) are a preclinical model of dry AMD. In this study, we performed a 4-month senolytic therapy with D + Q on 4-month-old Abca4-/-Rdh8-/- mice. Abca4-/-Rdh8-/- mice at the age of 8 months showed obvious retinal degeneration, along with RPE senescence, lysosomal alkalinization, lipofuscin accumulation and oxidative stress. Importantly, the long-term D + Q regimen significantly alleviated the degeneration of retinal structures and function in 8-month-old Abca4-/-Rdh8-/- mice, and it effectively repressed cellular senescence, lysosomal alkalinization, lipofuscin accumulation and oxidative stress in the RPE. This study is the first to demonstrate the effect of long-term intervention with senolytics D + Q on dry AMD. Overall, these findings highlight the potential of long-term senolytic treatment as an intervention for dry AMD.
    DOI:  https://doi.org/10.1016/j.redox.2025.103716
  10. Nat Med. 2025 Jun 09.
      
    Keywords:  Cancer; Clinical trials; Lifestyle modification
    DOI:  https://doi.org/10.1038/d41591-025-00038-4
  11. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2419762122
      The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a transcriptional regulator, responds to DNA damage by increasing the expression of the cyclin-dependent kinase inhibitor p21. p21 then arrests cells at specific stages of the cell cycle. Additionally, p53 upregulates serpinB2 (also known as plasminogen activator inhibitor-2, PAI-2), which stabilizes p21 in senescent cells. This study reveals that serpinB2 upregulation activates transglutaminase 2 (TGM2), which selectively deamidates multiple glutamine residues on p21, stabilizing the protein and halting cell proliferation in senescent cells. Moreover, inhibiting TGM2-mediated deamidation accelerates p21 degradation, delaying the onset of senescence. Notably, pharmacological inhibition of TGM2 improves aging phenotypes in an accelerated aging model of chronic kidney disease (CKD). These findings provide crucial insights into the role of TGM2-mediated enzymatic deamidation in senescence and its potential relevance to age-associated conditions.
    Keywords:  TGM2; p21; senescence; serpinB2
    DOI:  https://doi.org/10.1073/pnas.2419762122
  12. Cell Metab. 2025 Jun 09. pii: S1550-4131(25)00265-7. [Epub ahead of print]
      Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-coenzyme A (CoA) constitutes a small fraction of the whole-cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we report a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. Combining phenotypic chemical screen, genome-wide CRISPR screen, and proteomics, we identified that the nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively inhibited by the nuclear protein ELMSAN1 through direct interaction. Pharmacologic inhibition of the ELMSAN1-nPDC interaction derepressed nPDC activity, enhancing nuclear acetyl-CoA generation and reprogramming cancer cells to a postmitotic state with diminished cell-of-origin signatures. Reprogramming was synergistically enhanced by histone deacetylase 1/2 inhibition, resulting in inhibited tumor growth, durably suppressed tumor-initiating ability, and improved survival in multiple cancer types in vivo, including therapy-resistant sarcoma patient-derived xenografts and carcinoma cell line xenografts. Our findings highlight the potential of targeting ELMSAN1-nPDC as an epigenetic cancer therapy.
    Keywords:  ELMSAN1; HDAC; ISX9; acetyl-CoA metabolism; cancer therapy; compartmentalized metabolism; epigenetic reprogramming; nuclear metabolism; pyruvate dehydrogenase complex; therapeutic reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.009
  13. bioRxiv. 2025 May 26. pii: 2025.05.21.655403. [Epub ahead of print]
      Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these structures include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion in each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, along with their functional significance, are not well understood. Here, we investigate the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in shaping these structures and maintaining photoreceptor cell health. Rod photoreceptor cell-specific ablation of MFN1 and MFN2 resulted in mitochondrial fragmentation by one month of age, suggesting that mitochondrial fusion is essential for the development of photoreceptor cell-specific mitochondrial structures. Notably, the layer structures of the retina examined by light microscopy appeared unaffected at this age. Following this time period, significant photoreceptor cell degeneration occurred by three months of age. Furthermore, we showed that impaired mitochondrial fusion perturbed the balance of proteins involved in glycolysis, oxidative phosphorylation (OXPHOS), and β-oxidation, highlighting the critical role of mitochondrial fusion in ensuring the proper levels of proteins necessary for optimal energy metabolism. Additionally, we identified upregulation of cellular stress pathways such as endoplasmic reticulum (ER) stress and unfolded protein response (UPR), which arise in response to energy deprivation, and cytoprotective biosynthetic pathways mediated by CCAAT/enhancer-binding protein gamma (C/EBPγ) and mammalian target of rapamycin complex 1 (mTORC1) signaling. In summary, our findings indicate that mitochondrial fusion through MFN1 and MFN2 is vital for the development of unique mitochondrial structures and proper energy production, underscoring the fundamental importance of mitochondrial dynamics in photoreceptor cell function and survival.
    Significance Statements: Rod photoreceptor cells exhibit unique mitochondrial morphologies and high energy requirements. In this report, we examined how these unique mitochondrial structures are established and their biological significance. We identified that mitochondrial fusion is essential for the development of characteristic mitochondrial morphologies in rod photoreceptor cells. Furthermore, we demonstrated that impaired mitochondrial fusion disrupts the equilibrium of proteins associated with OXPHOS, glycolysis, and β-oxidation, ultimately leading to an imbalance in cellular energy homeostasis. Our findings also revealed activation of cellular stress pathways, including ER stress and the UPR, which are likely triggered by energy depletion. Additionally, we identified activation of cytoprotective biosynthetic pathways that are engaged to preserve cellular homeostasis and function.
    DOI:  https://doi.org/10.1101/2025.05.21.655403
  14. bioRxiv. 2025 Jun 01. pii: 2025.05.29.656153. [Epub ahead of print]
      Caloric restriction (CR) robustly extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketones, we decided to investigate the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2 , the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remains robust in mice lacking Hmgcs2 . To gain insight into why deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice began a CR diet. Surprisingly, as CR-fed mice adapt to CR, they no longer engage high levels of ketogenesis during the daily fast. Our work suggests that the benefits of long-term CR in mice are not mediated by ketogenesis.
    DOI:  https://doi.org/10.1101/2025.05.29.656153