bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–03–15
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Fasting Enhances Cardiomyocyte Hypoxia Tolerance by Regulating Ca2+ Transport at Mitochondria-Endoplasmic Reticulum Contact Sites.
  2. A lysosomal requiem for glioblastoma cells.
  3. Communication breakdown: senescent cells in interorgan communication of aging.
  4. Succinylation: A Functional Nexus Between Metabolic Reprogramming and Epigenetic Modifications in Cancer.
  5. β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
  6. Replicative senescence induction in single cells is not predicted by telomere length, dysfunction, or oxidation.
  7. Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.
  8. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  1. Int J Mol Sci. 2026 Feb 24. pii: 2117. [Epub ahead of print]27(5):
    Fasting Enhances Cardiomyocyte Hypoxia Tolerance by Regulating Ca2+ Transport at Mitochondria-Endoplasmic Reticulum Contact Sites.
    Xiangning Chen, Bo Jiao, Tong Xue, Manjiang Xie, Zhibin Yu.
      Mitochondria-endoplasmic reticulum contacts (MERCs) are physical structures formed between mitochondria and the endoplasmic reticulum (ER) through various tethering proteins, playing crucial roles in multiple physiological processes, including Ca2+ and lipid exchange between the ER and mitochondria, regulation of mitochondrial morphology and dynamics (fusion and fission), as well as the induction of autophagy and apoptosis. Mitofusin 2 (MFN2), a key mitochondrial fusion protein, has been identified as an essential structural component of MERCs. Our research demonstrates that 16:8 circadian intermittent fasting (CIF) leads to enhanced mitochondrial fusion. The upregulation of MFN2 reinforces MERC stability, thereby facilitating efficient Ca2+ transfer between the ER and mitochondria. This process sustains the activity of mitochondrial oxidative phosphorylation (OXPHOS) enzymes, elevates mitochondrial oxygen utilization efficiency, and ultimately augments ATP production. Consequently, these adaptations enhance cardiomyocyte tolerance to hypoxic conditions. This study elucidates a novel mechanism by which MERCs regulate cellular hypoxia resistance and proposes a potential therapeutic strategy for improving acute hypoxia tolerance through the modulation of Ca2+ transport at MERCs.
    Keywords:  MERC; calcium transport; cardiomyocyte; circadian intermittent fasting; hypoxia; mitofusin 2
    DOI:  https://doi.org/10.3390/ijms27052117
  2. Trends Cancer. 2026 Mar 11. pii: S2405-8033(26)00025-7. [Epub ahead of print]
    A lysosomal requiem for glioblastoma cells.
    Laura Merlet, Margaux Le Guyon, Julie Gavard.
      Once viewed solely as degradative compartments, lysosomes shape cell fate through signaling, metabolism, and communication. In glioblastoma, their rewiring underlies plasticity, invasion, and resistance to therapies. This forum explores lysosomal dynamics in brain tumors and therapeutic strategies targeting lysosomal vulnerabilities, offering fresh perspectives for precision approaches in this lethal cancer.
    Keywords:  autophagy; cell death; endolysosome; glioma; organelles
    DOI:  https://doi.org/10.1016/j.trecan.2026.01.012
  3. Trends Endocrinol Metab. 2026 Mar 10. pii: S1043-2760(26)00037-8. [Epub ahead of print]
    Communication breakdown: senescent cells in interorgan communication of aging.
    Rituparna Ghosh, Shweta S Dipali, Gabriela Desdín-Míco, Matthew J Yousefzadeh.
      Cellular senescence is a complex cell fate characterized by stable cell cycle arrest and other heterogeneous changes. Senescent cells play a causal role in aging, although the underlying mechanisms remain under active investigation. In this opinion article, we propose that senescent cells can act as key mediators of interorgan communication of aging. Recent work defines multifaceted mechanisms, including the production of senescence-associated secretory phenotype factors that act to propagate senescence signals to nearby and distant cells, as well as age-related alterations in immune function that drive chronic inflammation, known as 'inflammaging'. Further investigation of these mechanisms could yield improved strategies to target senescent cells and mitigate their effects on systemic aging via interorgan communication of aging.
    Keywords:  cellular senescence; immunosenescence; inflammaging; inflammation; interorgan aging
    DOI:  https://doi.org/10.1016/j.tem.2026.02.002
  4. Molecules. 2026 Feb 25. pii: 773. [Epub ahead of print]31(5):
    Succinylation: A Functional Nexus Between Metabolic Reprogramming and Epigenetic Modifications in Cancer.
    Dan Liu, Runtian Li, Mingzhu Li, Fang Xu, Ying Liang, Yang Sun.
      Metabolic reprogramming and epigenetic remodeling are critical features of tumorigenesis. The process of metabolic reprogramming causes metabolites like Succinyl-CoA to accumulate. Succinylation, which depends on succinyl-CoA as the direct donor group, plays a crucial role in regulating cancer metabolism. This involves the transfer of the succinyl group to the lysine residues of substrate proteins resulting in the alteration of the conformation and function of the proteins, modulating several signaling pathways, many of them involved in metabolism. There is growing evidence that succinylation can alter the activity and stability of metabolic enzymes and reshape metabolic networks. Furthermore, it precisely regulates gene expression through the epigenetic modification mechanisms of the histones and non-histone proteins. Lysine succinylation is thus a crucial hub linking tumor metabolic reprogramming and epigenetic remodeling. This review systematically summarizes the dynamic regulatory mechanisms of lysine succinylation and its critical roles in tumor metabolic reprogramming and epigenetic regulation. In the end, we discuss the crosstalk between succinylation and other post-translational modifications (PTMs) as well as recent advances in cancer therapies targeting succinylation.
    Keywords:  cancer; epigenetic modification; lysine succinylation; metabolic reprogramming; succinyl-CoA
    DOI:  https://doi.org/10.3390/molecules31050773
  5. Cell. 2026 Mar 06. pii: S0092-8674(26)00169-8. [Epub ahead of print]
    β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer.
    Shan Liu, Puneeth Guruprasad, Ranjani Ramasubramanian, Bhoomi Madhu, Luca Paruzzo, Kecheng Han, Andre Kelly, Alexander Shestov, He N Xu, Alberto Carturan, Chaoting Zhou, Kevin R Amses, Amichay Afriat, Lev Litichevskiy, Jason Lin, Ezra Dubowitz, Neil Tangal, Jing Zhang, Alana McSween, Melody Tan, Federico Stella, Andrew Lee, Siena Nason, Xianxin Hua, Michael Schneider, Madeleine Sleeman, Yunlin Zhang, Giulia Gabrielli, Ziqi Yang, Raymone Pajarillo, Ruchi Patel, Guido Ghilardi, Vrutti Patel, Akshita Joshi, Shunzhou Jiang, Yanqing Jiang, Patrizia Porazzi, Julia C Tchou, Brian Keith, Mingyao Li, Elise Chong, Stephen J Schuster, Michael Milone, Joshua Rabinowitz, Roddy S O'Connor, Christoph A Thaiss, Maayan Levy, Marco Ruella.
      The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.
    Keywords:  CAR T cell; cancer therapy; ketogenic diet; metabolism; oxidative phosphorylation; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.cell.2026.02.004
  6. iScience. 2026 Mar 20. 29(3): 114801
    Replicative senescence induction in single cells is not predicted by telomere length, dysfunction, or oxidation.
    Victor Passanisi, Sabrina L Spencer.
      The accumulation of senescent cells during aging contributes to age-associated diseases. Current models posit that replicative senescence is driven by telomere dysfunction, including telomere shortening, telomere-associated DNA damage response (DDR), and telomere oxidation. Here, we first show that aging primary human fibroblasts gradually increase the time spent in a CDK2-low non-cycling state and increase senescence biomarker expression. We then evaluate telomere features as single-cell senescence biomarkers in a workflow linking high-throughput, long-term time-lapse imaging with confocal imaging to map cell-cycle dynamics to telomere features in the same cell. Our results show that telomere length and DDR do not reliably distinguish cycling from non-cycling cells at any age, and that telomere oxidation is not associated with cell-cycle withdrawal. Instead, lysosomal content, cell size, genomic architecture, and p21 more reliably mark senescence induction, depicting replicative senescence as a complex state transition with currently measurable telomere features being weakly correlated with senescence.
    Keywords:  cell biology; functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114801
  7. Cancer Lett. 2026 Mar 11. pii: S0304-3835(26)00189-8. [Epub ahead of print] 218426
    Exploiting Metabolic Dependencies for Therapeutic Targeting of Brain Cancers.
    Emma Martell, Helgi Kuzmychova, Akaljot Grewal, Ujala Chawla, Charul Jain, Christopher M Anderson, Tanveer Sharif.
      Metabolic reprogramming is a defining hallmark of cancer, and brain tumors are no exception. The brain's extraordinary energy demands, metabolic compartmentalization, and protection by the blood-brain barrier create a unique microenvironment that profoundly shapes tumor metabolism. Many brain tumors exhibit enhanced glucose uptake and fermentative glycolysis, a phenomenon classically described as the Warburg effect. However, accumulating evidence over the past two decades reveals that brain tumors rely on a far broader and more dynamic metabolic repertoire. Beyond glycolysis, metabolic processes such as the pentose phosphate pathway, serine biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, glutaminolysis, lipid metabolism, and purine and pyrimidine biosynthesis, all contribute to sustaining tumor growth, stemness, epigenetic identity, and therapeutic resistance. These metabolic adaptations differ markedly across tumor types and developmental contexts, from glioblastoma and diffuse astrocytoma to oligodendroglioma, ependymoma, pediatric high-grade glioma, medulloblastoma, and other embryonal tumors. In this review, we provide an overview of the current understanding of the major metabolic hallmarks of brain cancer, emphasizing mechanisms that support tumor identity, proliferation, and survival. We further highlight emerging metabolic vulnerabilities and discuss progress in developing therapies that target these pathways. Together, these insights illuminate how metabolism underpins the remarkable adaptability of brain tumors and suggest new avenues for precision treatment.
    Keywords:  Cancer metabolism; brain tumors; epigenetics; metabolic therapy; tumor signaling
    DOI:  https://doi.org/10.1016/j.canlet.2026.218426
  8. Nat Commun. 2026 Mar 13.
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Cristina Vázquez-Muñoz, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. Here, to investigate strategies that alleviate mitochondrial dysfunction, we first generate a ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfamfl/flUbcCre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-chain fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share insufficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity, extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-70547-4
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