bims-cesemi 2025-01-12 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–01–12
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor

Mitochondria- and ER-associated actin are required for mitochondrial fusion.
Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
Functional Diversity of Senescent Cells in Driving Aging Phenotypes and Facilitating Tissue Regeneration.
Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.
A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.
Beyond the Hayflick limit: How microbes influence cellular aging.
CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.
α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.

Nat Commun. 2025 Jan 07. 16(1): 451

Mitochondria- and ER-associated actin are required for mitochondrial fusion.

Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.

Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.

DOI: https://doi.org/10.1038/s41467-024-55758-x
Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00487-X. [Epub ahead of print]37(1): 5-6

Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.

Sijie Tan, Nora Kory.

Mitochondria produce energy and building blocks essential for cell growth. How these competing processes are balanced and sustained during nutrient scarcity remains unclear. Ryu et al. uncover distinct mitochondrial subpopulations, one dedicated to ATP production and another to macromolecule synthesis, enabling cell growth and proliferation under nutrient-limiting conditions.

DOI: https://doi.org/10.1016/j.cmet.2024.12.006
J Biochem. 2025 Jan 06. pii: mvae098. [Epub ahead of print]

Functional Diversity of Senescent Cells in Driving Aging Phenotypes and Facilitating Tissue Regeneration.

Yasuhiro Nakano, Yoshikazu Johmura.

  As the global population continues to age, understanding the complex role of cellular senescence and its implications in healthy lifespans has gained increasing prominence. Cellular senescence is defined as the irreversible cessation of cell proliferation, accompanied by the secretion of a range of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP), in response to various cellular stresses. While the accumulation of senescent cells has been strongly implicated in the aging process and the pathogenesis of age-related diseases owing to their pro-inflammatory properties, recent research has also highlighted their essential roles in processes such as tumour suppression, tissue development, and repair. This review provides a comprehensive examination of the dual nature of senescent cells, evaluating their deleterious contributions to chronic inflammation, tissue dysfunction, and disease, as well as their beneficial roles in maintaining physiological homeostasis. Additionally, we explored the therapeutic potential of senolytic agents designed to selectively eliminate detrimental senescent cells while considering the delicate balance between transient and beneficial senescence and the persistence of pathological senescence. A deeper understanding of these dynamics is critical to develop novel interventions aimed at mitigating age-related dysfunctions and enhancing healthy life expectancies.

Keywords:  Age-related diseases; Cellular senescence; Healthspan; Senolytics; Tissue regeneration

DOI:  https://doi.org/10.1093/jb/mvae098
Cell Commun Signal. 2025 Jan 09. 23(1): 17

Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.

Xuexin Li, Xin Zhao, Zhengshan Qin, Jie Li, Bowen Sun, Li Liu.

  This review comprehensively explores the critical role of calcium as an essential small-molecule biomessenger in skeletal muscle function. Calcium is vital for both regulating muscle excitation-contraction coupling and for the development, maintenance, and regeneration of muscle cells. The orchestrated release of calcium from the endoplasmic reticulum (ER) is mediated by receptors such as the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R), which is crucial for skeletal muscle contraction. The sarcoendoplasmic reticulum calcium ATPase (SERCA) pump plays a key role in recapturing calcium, enabling the muscle to return to a relaxed state. A pivotal aspect of calcium homeostasis involves the dynamic interaction between mitochondria and the ER. This interaction includes local calcium signaling facilitated by RYRs and a "quasi-synaptic" mechanism formed by the IP3R-Grp75-VDAC/MCU axis, allowing rapid calcium uptake by mitochondria with minimal interference at the cytoplasmic level. Disruption of calcium transport can lead to mitochondrial calcium overload, triggering the opening of the mitochondrial permeability transition pore and subsequent release of reactive oxygen species and cytochrome C, ultimately resulting in muscle damage and atrophy. This review explores the complex relationship between the ER and mitochondria and how these organelles regulate calcium levels in skeletal muscle, aiming to provide valuable perspectives for future research on the pathogenesis of muscle diseases and the development of prevention strategies.

Keywords:  Atrophy; Calcium; Endoplasmic reticulum; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1186/s12964-024-02014-w
Biochim Biophys Acta Mol Cell Res. 2025 Jan 05. pii: S0167-4889(25)00005-9. [Epub ahead of print] 119900

A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells.

Martin Hirtl, Benjamin Gottschalk, Olaf A Bachkoenig, Furkan E Oflaz, Corina Madreiter-Sokolowski, Morten Andre Høydal, Wolfgang F Graier.

  The uptake of Ca2+ by mitochondria is an important and tightly controlled process in various tissues. Even small changes in the key proteins involved in this process can lead to significant cellular dysfunction and, ultimately, cell death. In this study, we used stimulated emission depletion (STED) microscopy and developed an unbiased approach to monitor the sub-mitochondrial distribution and dynamics of the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake 1 (MICU1) under resting and stimulated conditions. To visualize the inner mitochondrial membrane, the STED-optimized dye called pkMitoRed was used. The study presented herein builds on the previously verified exclusive localization of MICU1 in the intermembrane space, and that MCU moves exclusively laterally along the inner mitochondrial membrane (IMM). We applied a multi-angled arrow histogram to analyze the distribution of proteins within mitochondria, providing a one-dimensional view of protein localization along a defined distance. Combining this with optimal transport colocalization enabled us to further predict submitochondrial protein distribution. Results indicate that in HeLa cells Ca2+ elevation yielded MCU translocation from the cristae membrane (CM) to the inner boundary membrane (IBM). In AC16 cardiomyocyte cell line, MCU is mainly located at the IBM under resting conditions, and it translocates to the CM upon rising Ca2+. Our data describe a novel unbiased super-resolution image analysis approach. Our showcase sheds light on differences in spatial distribution dynamics of MCU in cell lines with different MICU1:MCU abundance.

Keywords:  Inner mitochondrial membrane (IMM); Mitochondrial calcium uniporter (MCU); Mitochondrial calcium uptake 1 (MICU1); Stimulated-emission depletion (STED); Structured illumination microscopy (SIM)

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119900
Ageing Res Rev. 2025 Jan 07. pii: S1568-1637(25)00003-0. [Epub ahead of print]104 102657

Beyond the Hayflick limit: How microbes influence cellular aging.

Mohammad Abavisani, Saba Faraji, Negar Ebadpour, Sercan Karav, Amirhossein Sahebkar.

  Cellular senescence, a complex biological process resulting in permanent cell-cycle arrest, is central to aging and age-related diseases. A key concept in understanding cellular senescence is the Hayflick Limit, which refers to the limited capacity of normal human cells to divide, after which they become senescent. Senescent cells (SC) accumulate with age, releasing pro-inflammatory and tissue-remodeling factors collectively known as the senescence-associated secretory phenotype (SASP). The causes of senescence are multifaceted, including telomere attrition, oxidative stress, and genotoxic damage, and they extend to influences from microbial sources. Research increasingly emphasizes the role of the microbiome, especially gut microbiota (GM), in modulating host senescence processes. Beneficial microbial metabolites, such as short-chain fatty acids (SCFAs), support host health by maintaining antioxidant defenses and reducing inflammation, potentially mitigating senescence onset. Conversely, pathogenic bacteria like Pseudomonas aeruginosa and Helicobacter pylori introduce factors that damage host DNA or increase ROS, accelerating senescence via pathways such as NF-κB and p53-p21. This review explores the impact of bacterial factors on cellular senescence, highlighting the role of specific bacterial toxins in promoting senescence. Additionally, it discusses how dysbiosis and the loss of beneficial microbial species further contribute to age-related cellular deterioration. Modulating the gut microbiome to delay cellular senescence opens a path toward targeted anti-aging strategies. This work underscores the need for deeper investigation into microbial influence on aging, supporting innovative interventions to manage and potentially reverse cellular senescence.

Keywords:  Aging; Cellular senescence; Microbiota; Oxidative stress

DOI:  https://doi.org/10.1016/j.arr.2025.102657
Nat Commun. 2025 Jan 09. 16(1): 541

CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.

Dorian V Ziegler, Kanishka Parashar, Lucia Leal-Esteban, Jaime López-Alcalá, Wilson Castro, Nadège Zanou, Laia Martinez-Carreres, Katharina Huber, Xavier Pascal Berney, María M Malagón, Catherine Roger, Marie-Agnès Berger, Yves Gouriou, Giulia Paone, Hector Gallart-Ayala, George Sflomos, Carlos Ronchi, Julijana Ivanisevic, Cathrin Brisken, Jennifer Rieusset, Melita Irving, Lluis Fajas.

The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.

DOI: https://doi.org/10.1038/s41467-024-55605-z
bioRxiv. 2024 Dec 26. pii: 2024.12.26.628172. [Epub ahead of print]

Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.

H Grace Rosen, Nicolas J Berger, Shantel N Hodge, Atsutaro Fujishiro, Jared Lourie, Vrusti Kapadia, Melissa A Linden, Eunbin Jee, Jonghan Kim, Yuho Kim, Kai Zou.

Although current treatments for Duchenne Muscular Dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2-mdx model of DMD (9-10 weeks old) with Mdivi-1, a selective Drp1 inhibitor, every other day (i.p. injection) for 5 weeks. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation and Fis1 in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-HNE, in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated Alpha 1 Type I Collagen (Col1a1) protein expression, a marker of fibrosis, and Interleukin-6 (IL-6) mRNA expression, a marker of inflammation. In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation.

DOI: https://doi.org/10.1101/2024.12.26.628172
Blood. 2024 Dec 27. pii: blood.2024025245. [Epub ahead of print]

α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.

Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris Iv, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J A Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia Ws Finley, Justin R Cross, Scott W Lowe.

Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.

DOI: https://doi.org/10.1182/blood.2024025245
bioRxiv. 2024 Dec 20. pii: 2024.12.19.629431. [Epub ahead of print]

Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.

Sarah Ding, Anisha Banerjee, Sara N Burke, Abbi R Hernandez.

Many of the 'hallmarks of aging' involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8-25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. AKT expression was significantly reduced in kTRF fed rats within liver and muscle tissue. However, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance. Within CA3, higher levels of FOXO1 gene expression correlated with poorer cognitive performance in ad libitum fed rats. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.

DOI: https://doi.org/10.1101/2024.12.19.629431