bims-cesemi 2026-10-25 papers

Issue of 2026–10–25
six papers selected by
Julio Cesar Cardenas, Universidad Mayor

Annu Rev Physiol. 2026 Oct 21.

Cellular Senescence in Skeletal Muscle: Molecular Mechanisms, Physiological Consequences, and Therapeutic Opportunities.

Rylee Kopchak, Nathan K LeBrasseur.

Cellular senescence is a stress-responsive cell fate characterized by stable growth arrest and acquisition of a proinflammatory senescence-associated secretory phenotype. Senescent cells accumulate with advancing age and contribute to dysfunction and disease across multiple organ systems. In skeletal muscle (SkM), emerging evidence indicates that senescence arises across diverse cell populations that collectively reshape the SkM niche. Through the SASP and altered intercellular signaling, senescent cells promote chronic inflammation, fibrosis, impaired regeneration, and metabolic dysfunction that contribute to SkM loss, SkM weakness, functional decline, and frailty. This review synthesizes current knowledge of the molecular drivers, hallmarks, and cellular origins of senescence within SkM and highlights the physiological consequences that extend from the cellular to the organismal level. We also discuss emerging senotherapeutic strategies that hold promise for optimizing SkM health and function with aging and disease.

DOI: https://doi.org/10.1146/annurev-physiol-040725-104324

Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123

Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.

Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.

When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.

Keywords: GLS; P5CS; metabolism; mitochondria; mtDNA

DOI: https://doi.org/10.1073/pnas.2613074123

Sci Adv. 2026 Oct 23. 12(43): eaed4541

Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs.

Cytotoxic chemotherapy typically results in the elimination of a fraction of the tumor with surviving cells entering a state of persistence or premature replicative senescence that can lead to recurrence. Here, we show that therapy-induced senescence is associated with robust up-regulation of Fas and/or TRAIL-R2/DR5 death receptors in vitro and in vivo. The latter receptors restricted entry to senescence and exerted selective pressure on senescent cells through promoting assembly of proapoptotic receptor-interacting protein kinase 1 (RIPK1)/Fas-associated death domain protein (FADD)/Caspase-8 "FADDosome" complexes, restrained by cFLIPL. Accordingly, deletion of CASP-8 robustly enhanced entry to senescence and prolonged the life span of senescent cells. cIAP-2, which inhibits death receptor-driven cell death, was also up-regulated in senescent cells, and deletion of IAPs suppressed entry to senescence. Consistent with this, small-molecule IAP antagonists exhibited potent senolytic activity through enhancing death receptor-initiated Caspase-8 activation. Thus, death receptor-driven assembly of RIPK1/FADD/Caspase-8 complexes in senescent cells orchestrates addiction to IAPs that can be exploited by IAP antagonists.

DOI: https://doi.org/10.1126/sciadv.aed4541

Science. 2026 Oct 22. 394(6822): 383-384

A cell death ballet in two acts.

Cristina Muñoz-Pinedo, Seamus J Martin.

Two proteins that permeabilize mitochondria promote cell death through distinct mechanisms.

DOI: https://doi.org/10.1126/science.aem1247

Science. 2026 Oct 22. 394(6822): eaea2181

BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.

Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.

The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.

DOI: https://doi.org/10.1126/science.aea2181