bims-cesemi 2026-09-13 papers

Cell Res. 2026 Sep 11.

Cell Metab. 2026 Sep 10. pii: S1550-4131(26)00339-6. [Epub ahead of print]

Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction.

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.

Keywords: PD-1; PD-L1; PD-L2; aging; cellular senescence; immune-related adverse events; immunotherapy; irAE; sPD-L2; senolytics

DOI: https://doi.org/10.1016/j.cmet.2026.08.014

Dev Cell. 2026 Sep 09. pii: S1534-5807(26)00315-1. [Epub ahead of print]61(9): 1747-1748

Senescent cells: Leaving cellular waste behind.

Hélène Martini, João F Passos.

Cellular senescence is one of the best-studied biological programs, yet it continues to reveal unexpected aspects. In this issue of Developmental Cell, Durik et al.1 describe how senescent cells shed large cytoplasmic fragments that promote their survival and may represent a mechanism of communication with neighboring cells.

DOI: https://doi.org/10.1016/j.devcel.2026.08.004

Nat Commun. 2026 Aug 13. pii: 9729. [Epub ahead of print]17(1):

InsP3R signaling and actomyosin-dependent mitochondrial dynamics play essential roles in mitochondrial stress-induced longevity.

Gaomin Feng, Elizabeth M Ruark, Alexandra G Mulligan, Eric K F Donahue, Anthony L Hoang, Brianne Jacquet-Cribe, Li Peng, Kristopher Burkewitz.

Certain forms of mitochondrial impairment confer longevity, while disease-associated mitochondrial dysfunction triggers pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. To explain this connection, we test multiple candidate links between Ca2+ and mitochondrial homeostasis previously established in vitro, including mitochondrial calcium uniporter (MCU)-dependent stimulation of respiration and cytosolic pathways regulating mitochondrial dynamics. We find that MCU is dispensable for both respiration and longevity in Complex I mutants. Conversely, transcriptomic profiling and imaging reveal InsP3R impairment results in maladaptive expansion of compromised mitochondrial networks. We provide evidence that this aberrant mitochondrial expansion results from disruption of a conserved, InsP3R-dependent actin remodeling network centered on Arp2/3. Disruption of actin remodeling or autophagy mimics the mitochondrial expansion and longevity suppression of InsP3R mutants. Conversely, driving mitochondrial fragmentation ameliorates mitochondrial expansion and rescues longevity in InsP3R mutants, supporting a model in which InsP3R-dependent actin remodeling is required for segregation and clearance of mitochondria. These findings identify an inter-organelle signaling axis linking ER calcium release and cytoskeletal remodeling to adaptive mitochondrial responses associated with longevity.

DOI: https://doi.org/10.1038/s41467-026-76514-3

Sci Adv. 2026 Sep 11. 12(37): eaeh2771

Metabolic regulation of calcium homeostasis via SERCA succination.

Su Jin Ham, Yena Kim, Sehyeon Kim, Sunhoe Bang, Young Hoon Koh, Soung-Hun Roh, Hyung Seo Park, Jongkyeong Chung.

Although calcium homeostasis is disrupted in metabolic diseases, its metabolic regulation remains unclear. Here, we identify a mechanism by which fumarate suppresses sarco/endoplasmic reticulum (ER) calcium ion-adenosine triphosphatase (SERCA) activity via succination of a conserved cysteine residue, impairing ER calcium uptake and promoting metabolic dysfunction in Drosophila. In mammalian cells, high glucose or fumarate inhibits SERCA activity and increases ER calcium release and cytosolic and mitochondrial calcium levels. Mechanistically, we show that fumarate covalently modifies SERCA2b at Cys875 and that a Cys875Ser mutant resists fumarate-induced inhibition. In Drosophila, knock-in flies with the corresponding Cys875Ser mutation preserve ER calcium homeostasis and are protected from hyperglycemia, glucose intolerance, and reduced survival on a high-sugar diet. These effects are phenocopied by pharmacological fumarate reduction or allosteric SERCA activation. Collectively, these findings suggest that fumarate-mediated SERCA inhibition provides a mechanistic link between glucose metabolism and calcium homeostasis, with potential relevance to metabolic dysfunction.

DOI: https://doi.org/10.1126/sciadv.aeh2771

Cell. 2026 Sep 11. pii: S0092-8674(26)00996-7. [Epub ahead of print]

Mitochondrial ATP promotes T cell differentiation through chromatin accessibility.

Immune elimination of chronic infection or cancer requires cytotoxic CD8+ T cells that adopt and maintain an effector phenotype. Cytotoxic T cell function is a bioenergetically demanding process. Here, we report the ability of D-α-hydroxybutyrate (DAHB) to act as a signaling molecule that increases mitochondrial ATP production and drives the conversion of proliferating T cells into cytotoxic effector cells. DAHB signaling switches ATP production from glycolysis to oxidative phosphorylation supported by fatty acid oxidation. This conversion elevates the level of a phosphagen, phosphocreatine (PCr). Both the PCr bioenergetic reserve and oxidative phosphorylation were required for T cell effector differentiation. DAHB-induced CD8 effector gene transcription was coupled to bioenergetics by BAF-complex-dependent remodeling of chromatin at effector loci. DAHB-enhanced CD8+ T cell antitumor activity both in vitro and in vivo. Together, these findings link cellular bioenergetics to the regulation of chromatin accessibility and gene expression required to support effector function.

Keywords: BAF; CD8 T cell effector function; D-alpha-hydroxybutyrate; OXPHOS; chromatin remodeling; creatine; phosphocreatine; tumor immunology

DOI: https://doi.org/10.1016/j.cell.2026.08.023