bims-cesemi 2026-03-08 papers

Issue of 2026–03–08
six papers selected by
Julio Cesar Cardenas, Universidad Mayor

Aging Cell. 2026 Mar;25(3): e70434

Decreased Glucose Metabolism and Declined Chaperones Are Unique Features Required for the Survival of Senescent Fibroblasts and Pyruvate Dehydrogenase Is a Potent Senolytic Target.

Mingzhu Zhang, Ziqi Hu, Shengwen Piao, Yingrui Song, Ying Jia, Jiaxing Liu, Ning Zhao, An Liu, Songbin Fu, Wenjing Sun, Hui Xu, Yu Yang, Steven P Gygi, Chunshui Zhou.

Cellular senescence contributes to aging and age-related diseases. Deep identifications of the senescence-specific cellular features are crucial to the better understanding of the survival and maintenance of senescence and the development of novel senolytics against senescent cells. By a global proteomic profiling of senescent human BJ fibroblasts induced by ionizing radiation, 178 cellular proteins with at least 4-fold or greater changes in abundance were identified, representing the cellular landscape of the senescent fibroblasts. Functional enrichments and biological experiments demonstrated that the decreased glucose metabolism, reduced ATP and alpha-KG production, and declined chaperones are the most striking features associated with senescent fibroblasts. Moreover, these proteomic features are closely correlated with their transcription alterations confirmed by RT-PCR. Respectively, inhibiting pyruvate dehydrogenase (critical enzyme to supply acetyl-CoA to TCA cycle) or glutaminase GLS1 (crucial enzyme to supplement TCA cycle intermediate alpha-KG) or inhibiting Hsp90 (important member of chaperones) led to the selective killing of senescent fibroblasts, indicating the essential roles of the TCA cycle or chaperones in the survival and maintenance of cellular senescence. Most importantly, co-inhibiting the TCA cycle and Hsp90 gave rise to the enhanced selective killing of senescent fibroblasts as well as the therapy-induced senescent cancer cells and the alleviation of physical dysfunctions in aged mice, suggesting the synergistic regulation of cellular senescence by the TCA cycle and chaperones. Thus, our profiling revealed key cellular features for the survival and maintenance in senescent normal cells, demonstrating that pyruvate dehydrogenase is a novel and potent senolytic target for the selective elimination of senescence.

Keywords: cellular senescence; chaperones; glucose metabolism; pyruvate dehydrogenase; senolytics; therapy‐induced senescence

DOI: https://doi.org/10.1111/acel.70434

Curr Opin Cell Biol. 2026 Mar 05. pii: S0955-0674(26)00015-3. [Epub ahead of print]100 102627

Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.

Akriti Prashar, Rosa Puertollano.

Mitochondria are highly dynamic and multifaceted organelles that perform essential cellular functions such as producing energy, regulating metabolism, and orchestrating immune responses. Lysosomes are crucial signaling hubs that are important for nutrient sensing, signal transduction, and regulation of cellular degradation and recycling processes including the removal of damaged mitochondrial components or entire mitochondria. Together, these two organelles perform critical cellular functions. Emerging evidence links defects in both organelles to multiple diseases, underscoring how their functions are intricately linked. To coordinate their activities, mitochondria and lysosomes engage in bidirectional crosstalk, enabling reciprocal regulation of their respective functions. These 'organelle conversations' can occur through direct interactions at membrane contact sites where both organelles physically interact via stabilization by molecular tethers, or at a distance through signaling pathways. Here we discuss recent progress in our understanding of the mechanisms underlying mitochondria-lysosome crosstalk and how this communication is altered in pathological conditions.

DOI: https://doi.org/10.1016/j.ceb.2026.102627

Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.

Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.

The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Keywords: ACO2; TCA cycle; cell metabolism; citrate; integrated stress response

DOI: https://doi.org/10.1016/j.cell.2026.01.028

Nat Aging. 2026 Mar 06.

Dietary restriction in aging and longevity.

Tomas Schmauck-Medina, Sofie Lautrup, Andrea Di Francesco, Sarah J Mitchell, Christoffer Clemmensen, Linda Partridge, George S Roth, Rozalyn M Anderson, Julie A Mattison, Rafael de Cabo, John R Speakman, Arlan Richardson, Donald K Ingram, Richard Weindruch, Mark P Mattson, Evandro F Fang.

Different types of dietary restriction (DR) have been practiced by humans for religious and medical purposes for millennia, but only during the past three decades has the scientific study of DR at cellular and molecular levels proliferated. Here we review the evidence testing a variety of DR paradigms in the context of aging, focusing on mammalian findings. We discuss potential DR mimetics that modulate autophagy, FGF21, AMPK, mTORC1, NAD+ metabolism, SIRTs, GLP-1R and other pathways as well as organismal and cellular adaptations to DR, including the roles of fasting, hunger, changes in body temperature and fat loss. We also consider the potential negative effects of DR such as increased vulnerability to infections and impaired wound healing. Further, we discuss preclinical evidence evaluating the potential of DR to improve healthspan and treat, prevent or delay age-related diseases including cancer, cardiovascular diseases and neurodegeneration. Finally, we consider the future opportunities for translation, and the challenges inherent to this complex research field.

DOI: https://doi.org/10.1038/s43587-026-01091-5

Mol Metab. 2026 Mar 02. pii: S2212-8778(26)00027-X. [Epub ahead of print] 102343

Photoreceptor deletion of pyruvate dehydrogenase E1 subunit α1 induces retinal degeneration and reprograms retinal metabolism.

Hongwei Ma, Lilliana R York, Shujuan Li, Grayson Gagnon, Junhuang Zou, Haoran Yu, Jun Yang, Yun Le, Mark Eminhizer, Isabella Mascari, Jianhai Du, Xi-Qin Ding.

Rod and cone photoreceptors are among the most energy-demanding cells in the body, exhibiting a high rate of ATP consumption. Their primary energy source is glucose, which is metabolized through both glycolysis and mitochondrial pyruvate oxidative phosphorylation. The pyruvate dehydrogenase E1 subunit α1 is a critical component of the pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl-CoA, thereby regulating mitochondrial pyruvate metabolism. To determine the significance of mitochondrial pyruvate metabolism in these cells, we investigated the impact of photoreceptor-specific Pdha1 deletion in the mouse retina. Rod- or cone-specific Pdha1 knockout mice at 2-4 months were used. These mice were evaluated across multiple modalities, including retinal structure and integrity (morphometry), retinal function (electroretinogram), photoreceptor ultrastructure (transmission electron microscopy), retinal metabolic profiles (mass spectrometry), gene expression (RT-PCR), and retinal stress response (glial activation analysis). Mice with rod- or cone-specific Pdha1 deletion exhibited retinal degeneration phenotype, manifested by impaired retinal morphology and light responses and significant retinal glial activation. Mechanistically, these retinas displayed profound metabolism reprogramming, evidenced by changes in key glycolysis and decreased tricarboxylic acid (TCA) cycle intermediates, carbohydrates, amino acids, nucleotides and their derivatives. This metabolic remodeling was further supported by enhanced glycolysis and decreased TCA cycle gene expression and was accompanied by impaired mitochondrial morphology. Our findings demonstrate that PDHA1 is essential for photoreceptor energy metabolism and for maintaining both their structural and functional integrity, thus highlighting the critical importance of proper mitochondrial glucose metabolism for photoreceptor health.

Keywords: Glucose metabolism; Mitochondrial metabolism; PDHA1; Photoreceptor; Photoreceptor metabolism; Pyruvate dehydrogenase; Pyruvate metabolism

DOI: https://doi.org/10.1016/j.molmet.2026.102343