bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–06–14
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. An INF2-dependent actin-mediated step in inositol 1,4,5-trisphosphate receptor cluster formation and activity.
  2. Circulating cell type senescence signatures track distinct dimensions of health status and trajectories in human longitudinal cohorts.
  3. Mitochondria tethered to the nucleus secure its energy supply.
  4. ERO1a fosters glioblastoma aggressiveness and metabolic flexibility by regulating mitochondria-associated membrane dynamics.
  5. Charting human cellular senescence in aging and disease.
  6. Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
  7. World-first: therapy to make cells young again trialled in a person.
  8. Mitochondria directly interact with the nuclear pore complex.
  9. Mitochondria-ER contacts function as an iron supply hub.
  10. Persistent and transient senescent cells contribute to brain-barrier development.
  11. Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle.
  12. A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.
  1. Curr Biol. 2026 Jun 08. pii: S0960-9822(26)00626-3. [Epub ahead of print]
    An INF2-dependent actin-mediated step in inositol 1,4,5-trisphosphate receptor cluster formation and activity.
    Maite R Zavala, Amrapali Ghosh, Suresh K Joseph, Rajarshi Chakrabarti.
      Intracellular calcium signaling plays a vital role in regulating various cellular processes including gene regulation, motility, metabolism, and cell death. Inositol 1,4,5-trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER) are a major cation channel that regulates stimulus-induced calcium release from the ER. While several molecular players regulate the activity of IP3R, its regulation by actin filaments was uncharacterized. Here, we show that actin filaments polymerized by the specific actin nucleator INF2 facilitate agonist-induced IP3R activity. Our results demonstrate that INF2-mediated actin filaments regulate the formation and/or stability of IP3R clusters on the ER that have been previously shown to be hotspots of ER calcium release. Using cell-biological and biochemical techniques, we further show that INF2 physically interacts with IP3R isoforms, often at IP3R clusters. While INF2-IP3R interaction is independent of INF2 activity, the ability of INF2 to mediate IP3R clusters is dependent on its actin polymerization activity. Finally, we demonstrate that in addition to its calcium mobilization activity, INF2 on the ER specifically regulates IP3R cluster positioning to mediate ER-mitochondrial contacts and facilitate ER-to-mitochondrial calcium transfer. Overall, these results reveal an actin-dependent step in the regulation of IP3R activity both in terms of ER calcium release and modulation of ER-mitochondrial contacts.
    Keywords:  ER calcium; ER-Mito contacts; INF2; IP3R; actin cytoskeleton
    DOI:  https://doi.org/10.1016/j.cub.2026.05.022
  2. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00467-5. [Epub ahead of print] 117389
    Circulating cell type senescence signatures track distinct dimensions of health status and trajectories in human longitudinal cohorts.
    Bradley Olinger, Carlos Anerillas, Allison B Herman, Dimitrios Tsitsipatis, Reema Banarjee, Toshiko Tanaka, Julian Candia, Manolis Maragkakis, Stefania Bandinelli, Keenan A Walker, Eleanor M Simonsick, Yue A Qi, Luigi Ferrucci, Myriam Gorospe, Nathan Basisty.
      Cellular senescence is implicated in age-related pathologies, and identifying circulating biomarkers of senescence holds great diagnostic potential. Circulating senescence signatures are predictive of age-related traits and diseases, though cell type senescence signatures have not been comprehensively explored. In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types are examined in circulation for clinical relevance in two longitudinal studies-1,275 participants of the Baltimore Longitudinal Study of Aging (BLSA) and 997 participants of the Invecchiare in Chianti (InCHIANTI) study. Notably, pooled senescence proteins outperform non-senescence proteins in predicting many clinical parameters such as age and hypertension, and in many instances, cell type senescence signatures map most strongly to their corresponding health domain. Importantly, the immune cell senescence signature is associated with mortality and future disease onset. This study demonstrates that circulating cell type biomarkers of senescence can reveal higher resolution health status than previously attained.
    Keywords:  CP: metabolism; biomarkers; geroscience; multi-omics; plasma; proteomics; senescence; senotype; transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2026.117389
  3. Nature. 2026 Jun;654(8119): 605-606
    Mitochondria tethered to the nucleus secure its energy supply.
    Philippa Clarke, Sophie Trefely.
      
    Keywords:  Cell biology; Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-01587-5
  4. Nat Cell Biol. 2026 Jun 12.
    ERO1a fosters glioblastoma aggressiveness and metabolic flexibility by regulating mitochondria-associated membrane dynamics.
    Arthur Bassot, Lola Violy, Lucas Gorka, Lavinia Cigalotto, Balasubramaniam Namasivayam, Ivan Mikaelian, Emma St Johnston, Chao Han, Rudy Gadet, Beatrice Alpha-Bazin, Laurine Moindrot, Emilie Clement, Helena Dragic, Marine Crépin, Olivier Berdeaux, Christophe Vanbelle, Mélina Gautier, Alice Cariou, Louis Larrouquere, Chunmei Wei, Thomas Gudermann, Jann N Sarkaria, Ester Zito, Pierre-Yves Dietrich, Paul R Walker, Ivan Nemazanyy, Hubert Lincet, Jean Armengaud, Jennifer Rieusset, Paul S Mischel, Elmina Mammadova-Bach, Thomas Simmen, Denis Martinvalet, Marie Castets, Erika Cosset.
      Despite the wealth of data generated in the omics era to investigate molecular drivers, glioblastoma (GBM) remains one of the most incurable cancers with a poor median of survival. Here we unravelled the dynamic crosstalk between the endoplasmic reticulum and mitochondria, known as mitochondria-associated membranes (MAMs) and define how modulation of calcium fluxes and MAM structure influences GBM cell plasticity and metabolic flexibility. We identified ERO1α, whose expression is significantly associated with poor GBM patient survival, as a critical MAM protein that regulates MAM structure, dynamics and calcium-mediated functions. Our data demonstrate that ERO1α activity and expression promotes GBM aggressiveness in vitro and in vivo and enhances mitochondrial oxidative phosphorylation. By establishing a direct link between ERO1α-mediated MAM modulation and the antitumour effects of ERO1α inhibition, this work highlights a context-dependent, druggable vulnerability that can be exploited for GBM therapy.
    DOI:  https://doi.org/10.1038/s41556-026-01980-2
  5. Cell. 2026 Jun 11. pii: S0092-8674(26)00587-8. [Epub ahead of print]189(12): 3501-3505
    Charting human cellular senescence in aging and disease.
    NIH SenNet consortium
      Cellular senescence comprises diverse cell states emerging across human tissues during aging and disease. Integrating single-cell and spatial multi-omics with AI-driven analyses enables systematic mapping of senescent cell heterogeneity ("senotypes"), revealing tissue-specific programs and microenvironmental interactions. These advances provide frameworks for biomarker discovery and development of targeted senotherapeutic strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.028
  6. Nat Commun. 2026 Jun 12.
    Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
    Ou Jiang, Zichen Cao, Sihan Kong, Qibing Wu, Tianyi Zhang, Xinyue Chen, Bo Zhou, Yao Feng, Songyue Wu, Jinsong Wang, Mo Chen, Xiaoyu Li, Songlin Wang.
      White adipose browning is a promising route to restore energy balance; however, how inorganic anion signals engage intracellular organelle networks to drive this process remains unclear. Here, we identify Sialin2 as a nitrate sensor that converts dietary nitrate into a spatially confined thermogenic program by coupling ER-mitochondria Ca2+ transfer with lipid routing into mitochondrial oxidation. Sialin2 localizes to mitochondria and the endoplasmic reticulum (ER), where it strengthens ER-mitochondria contacts and engages the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter 1 (MCU1) conduit to enhance inducible mitochondrial Ca2+ uptake. In parallel, Sialin2 associates with lysosomal acid lipase (LIPA), acyl-CoA synthetase long-chain family member 3 (ACSL3), and carnitine palmitoyltransferase 1 A (CPT1A) to channel lipid-droplet-derived fatty acids into β-oxidation, thereby fueling the tricarboxylic acid cycle and uncoupling protein 1 (UCP1)-dependent respiration. Loss of Slc17a5 abolishes nitrate-evoked browning and metabolic benefits, whereas nitrate supplementation improves adipose thermogenesis and systemic metabolic indices in male mice with diet-induced obesity without adrenergic stimulation. Together, these findings identify an organelle-specific nitrate-sensing mechanism that couples inorganic anion signalling to substrate routing in adipocytes and establish a non-hormonal pathway for restoring metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74256-w
  7. Nature. 2026 Jun 09.
    World-first: therapy to make cells young again trialled in a person.
    Heidi Ledford.
      
    Keywords:  Ageing; Cell biology; Epigenetics
    DOI:  https://doi.org/10.1038/d41586-026-01836-7
  8. Nature. 2026 Jun 10.
    Mitochondria directly interact with the nuclear pore complex.
    Ivan Menendez-Montes, Consuelo Marin-Vicente, Shibani Mukherjee, Mahmoud Salama Ahmed, Manuel Jose Gomez, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Svenja Koslowski, Ashley Solmonson, Tara Tassin, Shah R Ali, Pedro Pessoa, Abdallah Elnwasany, Nicholas T Lam, Suwannee Thet, Enrique Calvo, Alisson C Cardoso, Ana Helena M Pereira, Feng Xiao, Ping Wang, Asim Mohamed, Hamed El-Feky, Ahmed Elghamry, Gonzalo Gancedo-Alonso, Ngoc Uyen Nhi Nguyen, Ching-Cheng Hsu, Aundrea K Westfall, Ralph DeBerardinis, Roger Sik-Yin Foo, Michael Kinter, Steve Pressé, Chao Xing, Luke Szweda, Asaithamby Aroumougame, Fatima Sanchez-Cabo, Jose Antonio Enriquez, Miguel Torres, Jesus Vazquez, Hesham A Sadek.
      Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
    DOI:  https://doi.org/10.1038/s41586-026-10588-3
  9. Nat Cell Biol. 2026 Jun 10.
    Mitochondria-ER contacts function as an iron supply hub.
    Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
    DOI:  https://doi.org/10.1038/s41556-026-01974-0
  10. Cell. 2026 Jun 10. pii: S0092-8674(26)00581-7. [Epub ahead of print]
    Persistent and transient senescent cells contribute to brain-barrier development.
    L Ashley Watson, Zoe Adelsheim, Mackenzie J Carter, Grace T Carter, Karen L Jimenez-Reyes, Huijie Du, Ziqing Zhu, David B Berry, Mia C Paredez, Rania H Palaniappan, John M Augustine, Hiruy S Meharena.
      Establishment of the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier requires precise coordination between diverse cell types to protect and nourish the brain. Here, we identify developmentally programmed p21+ senescent cells that exhibit divergent senescence-associated features across these two brain interfaces in mice. In the choroid plexus (ChP), epithelial cells adopt a lifelong, non-inflammatory senescent state associated with CSF production and blood-CSF barrier integrity. In contrast, vascular endothelial cells and brain-resident macrophages transiently exhibit pro-inflammatory senescence profiles during brain vascularization, with reciprocal signaling linked to angiogenic patterning and extracellular matrix assembly. The ablation of p21+ cells during mid-gestation disrupts brain vascular patterning and ChP integrity, which results in hemorrhage, impaired CSF production, and ventricular collapse. These findings indicate that embryonic senescent cells adopt divergent transient and long-lived states that support brain-barrier formation and homeostasis, thus reframing the prevailing view of persistent senescence beyond solely a pathological state.
    Keywords:  blood-brain barrier; blood-cerebrospinal fluid barrier; brain development; brain-resident macrophages; choroid plexus; senescence; vascular endothelial cells
    DOI:  https://doi.org/10.1016/j.cell.2026.05.022
  11. Science. 2026 Jun 11. eadv8291
    Chemically induced skin tumors arise from long-lived stem cells of the upper hair follicle.
    Eve Kandyba, Arnaud Jabouille, Ferriol Calvet, Yun Rose Li, Andrea Curtabbi, Diana Cristea, Joyce Shin, Reyno Delrosario, Jonathan Anzules, Di Wu, David Quigley, Mark Taylor, Camila Zanette, Fang Yin Lo, Jacob Higgins, Jesse Salk, Nuria Lopez-Bigas, Allan Balmain.
      The identification of the cancer cell of origin is a fundamental question in cancer biology. We used fluorescent lineage tracing of independent mouse skin stem cell populations, single cell transcriptomics, and Duplex sequencing, to identify the origin of chemically induced skin tumors. Tumors arose predominantly from Lgr6+ and / or Lrig1+ stem cells of the upper hair follicle, but only very rarely from the Lgr5+ and Krt19+ hair follicle bulge. Lgr6+ stem cells initiated by dimethylbenzanthracene responded to tumor promoter treatment resulting in clonal expansion of initiated cells carrying the canonical Hras Q61L mutation. Spontaneous mutations in Kras also clonally expanded, but did not generate tumors unless the Hras gene was deleted, thus revealing a competitive interaction between Hras and Kras pathways that influences clonal selection.
    DOI:  https://doi.org/10.1126/science.adv8291
  12. Sci Adv. 2026 Jun 12. 12(24): eadz1953
    A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.
    Chrysovalantou E Xirouchaki, Esther García-Domínguez, Eamon Coughlan, Meagan J McGrath, Saveen Giri, Shuwei Liang, Florian Wiede, Anne Bigot, Junichi Sadoshima, Maria C Gomez-Cabrera, Andrew Philp, Marcus Moberg, William Apró, William Roman, Christina A Mitchell, Tony Tiganis.
      A decline in nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function. We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.
    DOI:  https://doi.org/10.1126/sciadv.adz1953
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