bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–05–04
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.
  2. Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
  3. Cellular senescence in age-related musculoskeletal diseases.
  4. Deletion of Nrf1α exacerbates oxidative stress-induced cellular senescence by disrupting cell homeostasis.
  5. Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
  6. 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
  7. Predictive modeling of glioblastoma recurrence for therapeutic target identification.
  8. Plasma senescence associated secretory proteins: A new link to mild cognitive impairment.
  9. Altering metabolism programs cell identity via NAD+-dependent deacetylation.
  10. NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
  11. Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
  1. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00398-5. [Epub ahead of print]44(5): 115627
    Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.
    Jillian S Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z Stanger, Anil K Rustgi, Jason R Pitarresi, J Kevin Foskett.
      Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.
    Keywords:  CP: Cancer; CP: Metabolism; EMT; MCU; PDAC; calcium signaling; cancer; epithelial-to-mesenchymal transition; metabolism; mitochondria; pancreas; uniporter
    DOI:  https://doi.org/10.1016/j.celrep.2025.115627
  2. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251332141
    Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
    Jason C Casler, Matilde V Neto, Thomas Burgoyne, Laura L Lackner.
      Sites of close apposition between organelles, known as membrane contact sites (MCSs), are critical regulators of organelle function. Mitochondria form elaborate reticular networks that perform essential metabolic and signaling functions. Many mitochondrial functions are regulated by MCSs formed between mitochondria and other organelles. In this review, we aim to bring attention to an understudied, but physiologically important, MCS between mitochondria and the plasma membrane (PM). We first describe the molecular mechanism of mitochondria-PM tethering in budding yeast and discuss its role in regulating multiple biological processes, including mitochondrial dynamics and lipid metabolism. Next, we discuss the evidence for mitochondria-PM tethering in higher eukaryotes, with a specific emphasis on mitochondria-PM contacts in retinal cells, and speculate on their functions. Finally, we discuss unanswered questions to guide future research into the function of mitochondria-PM contact sites.
    Keywords:  cell biology; electron microscopy; interorganelle (inter-organelle); membrane contact sites (MCSs)‌; mitochondrion (mitochondria); plasma membrane
    DOI:  https://doi.org/10.1177/25152564251332141
  3. Front Med. 2025 May 02.
    Cellular senescence in age-related musculoskeletal diseases.
    Jinming Xiong, Qiaoyue Guo, Xianghang Luo.
      Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculoskeletal diseases, including osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. The detrimental effects of senescence are primarily due to impaired regenerative capacity of stem cells and the pro-inflammatory environment created by accumulated senescent cells. The secreted senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, further amplifying senescent signals. Although the removal of senescent cells and the suppression of SASP factors have shown promise in alleviating disease progression and restoring musculoskeletal health in mouse models, clinical trials have yet to demonstrate significant efficacy. This review summarizes the mechanisms of cellular senescence in age-related musculoskeletal diseases and discusses potential therapeutic strategies targeting cellular senescence.
    Keywords:  aging; cellular senescence; degenerative diseases; musculoskeletal disease; senotherapy
    DOI:  https://doi.org/10.1007/s11684-025-1125-7
  4. Biochim Biophys Acta Mol Cell Res. 2025 Apr 23. pii: S0167-4889(25)00075-8. [Epub ahead of print]1872(6): 119970
    Deletion of Nrf1α exacerbates oxidative stress-induced cellular senescence by disrupting cell homeostasis.
    Da Lyu, Meng Wang, Lu Qiu, Rongzhen Deng, Shaofan Hu, Yiguo Zhang.
      Cellular senescence is recognized as a fundamental hallmark contributing to ageing and various age-related diseases, with oxidative stress playing a critical initiating role in their pathological processes. However, the anti-senescence potential of the antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded by Nfe2l1) remains elusive, despite accumulating evidence demonstrating its role as an indispensable redox-determining transcription factor for maintaining cellular homeostasis and organ integrity. This study reveals that deletion of Nrf1α significantly elevates senescence characteristics in Nrf1α-/--deficient cells, as evidenced by two distinct experimental models. These cells exhibit heightened activity of senescence-associated β-galactosidase and progressive senescence-associated secretory phenotype (SASP), accompanied by decreased cell vitality and intensified cell cycle arrest. Further investigation uncovers that this acceleration of oxidative stress-induced senescence results from increased disturbance in cellular homeostasis. The Nrf1α-/- deficiency leads to STAG2- and SMC3-dependent chromosomal stability disruption and autophagy dysfunction, albeit being accompanied by excessive accumulation of Nrf2 (encoded by Nfe2l2). The aberrantly hyperactive Nrf2 cannot effectively counteract the escalating disturbance of cellular homeostasis caused by Nrf1α-/-. This study provides evidence supporting Nrf1α's essential cytoprotective function against stress-induced cellular senescence, highlighting its indispensable contribution to maintaining robust cell homeostasis during the senescence pathophysiological process.
    Keywords:  Anti-ageing; Autophagy; Cellular homeostasis; Chromosomal instability; Nrf1; Nrf2; Oxidative stress; SMC3; STAG2; Senescence
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119970
  5. Nat Metab. 2025 Apr 28.
    Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
    Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.
      During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.
    DOI:  https://doi.org/10.1038/s42255-025-01289-8
  6. Aging Cell. 2025 Apr 25. e70054
    3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
    Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton.
      Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.
    Keywords:  3D reconstruction; MFN‐2; aging; exercise; human skeletal muscle; mitochondria
    DOI:  https://doi.org/10.1111/acel.70054
  7. EMBO Mol Med. 2025 Apr 28.
    Predictive modeling of glioblastoma recurrence for therapeutic target identification.
    Hrvoje Miletic, Thomas Daubon.
      
    DOI:  https://doi.org/10.1038/s44321-025-00236-0
  8. J Nutr Health Aging. 2025 Apr 24. pii: S1279-7707(25)00085-5. [Epub ahead of print]29(5): 100561
    Plasma senescence associated secretory proteins: A new link to mild cognitive impairment.
    Reema Banarjee, Nathan Basisty.
      
    DOI:  https://doi.org/10.1016/j.jnha.2025.100561
  9. EMBO J. 2025 Apr 25.
    Altering metabolism programs cell identity via NAD+-dependent deacetylation.
    Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, Joshua M Brickman.
      Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.
    Keywords:  Aging; Enhancers; Metabolism; Pluripotency; Sirtuins
    DOI:  https://doi.org/10.1038/s44318-025-00417-0
  10. Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]
    NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
    Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.
      Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
    Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
  11. Nat Commun. 2025 Apr 29. 16(1): 4029
    Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
    Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.
      Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.
    DOI:  https://doi.org/10.1038/s41467-025-59427-5
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