bims-cesemi 2025-08-10 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–08–10
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor

Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.
IP3-mediated Ca2+ transfer from ER to mitochondria stimulates ATP synthesis in primary hippocampal neurons.
Senescent cell heterogeneity and responses to senolytic treatment are related to cell cycle status during senescence induction.
Stromal senescence contributes to age-related increases in cancer.
Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.
NADH reductive stress drives metabolic reprogramming.
How animal paw pads got their toughness.
The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.
The senescence-inhibitory p53 isoform Δ133p53α: enhancing cancer immunotherapy and exploring novel therapeutic approaches for senescence-associated diseases.
SkeletAge: Transcriptomics-based Aging Clock Identifies 26 New Targets in Skeletal Muscle Aging.

Cell Calcium. 2025 Jul 19. pii: S0143-4160(25)00065-X. [Epub ahead of print]131 103056

Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.

Sara A Garcia, Anne M Neumaier, Michael Kohlhaas, Anton Xu, Alexander Nickel, Katharina J Ermer, Luzia Enzner, Christoph Maack, Vasco Sequeira, Christopher N Johnson.

  Mitochondrial calcium (Ca2+) uptake and factors that regulate this process have been an area of immense interest given the roles in cellular energetics. Here, we have investigated the ability of the Ca2+ sensing protein Calmodulin (CaM) to modify the function of the Mitochondrial Ca2+ Uniporter (MCU). Our data leveraged recombinantly produced CaM and mitochondria isolated from healthy and MCU impaired/diseased mice (Barth syndrome model). We found CaM enhanced Ca2+ uptake in both the absence and presence of CaMKII inhibition (KN93 as well as AIP). Mitochondria lacking function MCU (Barth syndrome model) validated that MCU was responsible for Ca2+ uptake in our experiments. Control experiments demonstrate that the observed CaM enhancement does not arise from CaM Ca2+ buffering. Fitting the Ca2+fluorescence data supported a monophasic decay process where the presence of CaM yielded enhanced kinetic rates of Ca2+ uptake. This CaM enhancement effect persisted in the presence of PTP impairment (cyclosporin), and subtle modification to the CaM protein sequence (D131E) revealed that an intact CaM-C domain Ca2+ binding was required for enhancement of MCU function.

Keywords:  Calcium; Calmodulin; Calmodulin dependent kinase II (CaMKII); Mitochondrial calcium uniporter (MCU); Permeability transition pore (PTP)

DOI:  https://doi.org/10.1016/j.ceca.2025.103056
Neuropharmacology. 2025 Aug 06. pii: S0028-3908(25)00334-X. [Epub ahead of print] 110626

IP3-mediated Ca2+ transfer from ER to mitochondria stimulates ATP synthesis in primary hippocampal neurons.

Ankit Dhoundiyal, Vanessa Goeschl, Stefan Boehm, Helmut Kubista, Matej Hotka.

  During electrical activity, Ca2+ enhances mitochondrial ATP production, helping to replenish the energy consumed during this process. Most Ca2+ enters the cell via ligand- or voltage-gated channels on the neuronal membrane, where it stimulates the release of additional Ca2+ from the endoplasmic reticulum (ER). Although the influence of cytosolic Ca2+ on neuronal metabolism has been widely investigated, relatively few studies have explored the contribution of ER Ca2+ release in this context. Therefore, we investigated how activity-driven Ca2+ crosstalk between the ER and mitochondria influences the regulation of mitochondrial ATP production. We show that in primary hippocampal neurons derived from rat pups of either sex, depletion of ER Ca2+ led to a reduction in mitochondrial Ca2+ levels during both resting and stimulated states, while exerting only a minimal impact on cytosolic Ca2+ levels. Additionally, impaired ER-mitochondria Ca2+ transfer led to a reduction in mitochondrial ATP production. Similar effects were observed when inositol-3-phosphate receptors (IP3Rs), but not ryanodine receptors (RyRs), were pharmacologically inhibited. Together, our findings show that, in hippocampal neurons, Ca2+ is transferred from the ER to mitochondria through IP3 receptors, and this Ca2+ crosstalk in turn enhances mitochondrial ATP production in response to neuronal activity.

Keywords:  ATP; ER calcium; IP(3)Rs; RyRs; mitochondria; neuronal metabolism

DOI:  https://doi.org/10.1016/j.neuropharm.2025.110626
Aging (Albany NY). 2025 Aug 07. 17

Senescent cell heterogeneity and responses to senolytic treatment are related to cell cycle status during senescence induction.

Francesco Neri, Shuyuan Zheng, Mark A Watson, Pierre-Yves Desprez, Akos A Gerencser, Judith Campisi, Denis Wirtz, Pei-Hsun Wu, Birgit Schilling.

  Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2-arrested senescent cells feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.

Keywords:  cell cycle; cellular senescence; heterogeneity; imaging; senolytics

DOI:  https://doi.org/10.18632/aging.206299
Nat Rev Cancer. 2025 Aug 04.

Stromal senescence contributes to age-related increases in cancer.

Jiayu Ye, Anupama Melam, Sheila A Stewart.

Ageing is a process characterized by a wide array of cellular and systemic changes that together increase the risk of developing cancer. While cell-autonomous mutations within incipient tumour cells are important, age-related changes in the microenvironment are critical partners in the transformation process and response to therapy. However, aspects of ageing that are important and the degree to which they contribute to cancer remain obscure. One of the factors that impacts ageing is increased cellular senescence but it is important to note that ageing and cellular senescence are not synonymous. We highlight open questions, including if senescent cells have phenotypically distinct impacts in aged versus young tissue, or if it is the cell type that dictates the impact of senescence on tissue homeostasis and disease. Finally, it is probable that our current definition of cellular senescence encompasses more than one mechanistically distinct cellular state; thus, we highlight phenotypic differences that have been noted across cell types and tissues of origin. This Review focuses on the role that senescent stromal cells have in cancer, with a particular emphasis on fibroblasts given the amount of work that has focused on them.

DOI: https://doi.org/10.1038/s41568-025-00840-9
bioRxiv. 2025 Aug 02. pii: 2025.08.01.668243. [Epub ahead of print]

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.

Adarsh Rajesh, Aaron P Havas, Rouven Arnold, Kathryn Lande, K Garrett Evensen, Kelly Yichen Li, Sainath Mamde, Qian Yang, Armin Gandhi, Karl N Miller, Marcos Garcia Teneche, Zoe Yao, Jessica Proulx, Andrew Davis, Laurence Haddadin, Michael Alcaraz, Carolina Cano Macip, Brightany Li, Xue Lei, Charlene Miciano, Elizabeth Smoot, Allen Wang, Jeffrey H Albrecht, April E Williams, Bing Ren, Kevin Y Yip, Peter D Adams.

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

DOI: https://doi.org/10.1101/2025.08.01.668243
Trends Cell Biol. 2025 Aug 05. pii: S0962-8924(25)00157-6. [Epub ahead of print]

NADH reductive stress drives metabolic reprogramming.

Ronghui Yang, Zihao Guo, Binghui Li.

  Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD+ couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.

Keywords:  NADH reductive stress; NADH-reductive-stress-associated diseases; energy stress; metabolic reprogramming; oxidative stress

DOI:  https://doi.org/10.1016/j.tcb.2025.07.005
Nature. 2025 Aug 08.

How animal paw pads got their toughness.



Keywords:  Cell biology

DOI:  https://doi.org/10.1038/d41586-025-02474-1
Annu Rev Cell Dev Biol. 2025 Aug 06.

The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.

Nazma Malik, Reuben J Shaw.

Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.

DOI: https://doi.org/10.1146/annurev-cellbio-120420-094431
Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00321-0. [Epub ahead of print]86 103808

Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics.

Jose Adan Arevalo, Dianna Xing, Roberto Garcia Leija, Max A Thorwald, Diana Daniela Moreno-Santillán, Kaitlin N Allen, Giovanna Selleghin-Veiga, Heidi C Avalos, Eva Utke, Justin L Conner, George A Brooks, José Pablo Vázquez-Medina.

An age-related decline in mitochondrial function is a multi-factorial hallmark of aging, driven partly by increased lipid hydroperoxide levels that impair mitochondrial respiration in skeletal muscle, leading to atrophy. Although pharmacological and genetic manipulations to counteract increased lipid hydroperoxide levels represent a promising strategy to treat sarcopenia, the mechanisms driving such phenotypes remain understudied. Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that contributes to peroxidized membrane repair via its phospholipid hydroperoxidase and phospholipase A2 activities. Here, we show decreased mitochondrial Prdx6 levels, increased mitochondrial lipid peroxidation, and dysregulated muscle bioenergetics in aged mice and muscle cells derived from older humans. Mechanistically, we found that Prdx6 supports optimal mitochondrial function and prevents mitochondrial fragmentation by limiting mitochondrial lipid peroxidation via its membrane remodeling activities. Our results suggest that age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics, thereby opening the door to therapeutic modulation of Prdx6 to counteract diminished mitochondrial function in aging.

DOI: https://doi.org/10.1016/j.redox.2025.103808
Geroscience. 2025 Aug 06.

The senescence-inhibitory p53 isoform Δ133p53α: enhancing cancer immunotherapy and exploring novel therapeutic approaches for senescence-associated diseases.

Shinji Nakamichi, Leo Yamada, Christopher Roselle, Izumi Horikawa, Carl H June, Curtis C Harris.

  Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.

Keywords:  Cellular senescence; Chimeric antigen receptor T cells; Progeria; Pulmonary fibrosis; Transgenic mice; Δ133p53α

DOI:  https://doi.org/10.1007/s11357-025-01819-y
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667277. [Epub ahead of print]

SkeletAge: Transcriptomics-based Aging Clock Identifies 26 New Targets in Skeletal Muscle Aging.

Muhammad Ali, Fei Li, Manpreet Katari.

Identifying the set of genes that regulate baseline healthy aging - aging that is not confounded by illness - is critical to understating aging biology. Machine learning-based age-estimators (such as epigenetic clocks) offer a robust method for capturing biomarkers that strongly correlate with age. In principle, we can use these estimators to find novel targets for aging research, which can then be used for developing drugs that can extend the healthspan. However, methylation-based clocks do not provide direct mechanistic insight into aging, limiting their utility for drug discovery. Here, we describe a method for building tissue-specific bulk RNA-seq-based age-estimators that can be used to identify the ageprint . The ageprint is a set of genes that drive baseline healthy aging in a tissue-specific, developmentally-linked fashion. Using our age estimator, SkeletAge, we narrowed down the ageprint of human skeletal muscles to 128 genes, of which 26 genes have never been studied in the context of aging or aging-associated phenotypes. The ageprint of skeletal muscles can be linked to known phenotypes of skeletal muscle aging and development, which further supports our hypothesis that the ageprint genes drive (healthy) aging along the growth-development-aging axis, which is separate from (biological) aging that takes place due to illness or stochastic damage. Lastly, we show that using our method, we can find druggable targets for aging research and use the ageprint to accurately assess the effect of therapeutic interventions, which can further accelerate the discovery of longevity-enhancing drugs.

DOI: https://doi.org/10.1101/2025.07.28.667277