bims-cesemi 2025-05-18 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–05–18
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor

To transfer mitochondria or not to transfer mitochondria: ADP does the trick.
Mitochondria-membranous organelle contacts at a glance.
MICU1 is the nexus for CaV3.3 regulation of mitochondrial calcium, redox balance and chondrocyte viability.
Using novel oxidative phosphorylation inhibitors to attenuate drug resistance in human gliomas.
Split genetically encoded calcium indicators for interorganellar junctions.
Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.
Saikosaponin A induces cellular senescence in triple-negative breast cancer by inhibiting the PI3K/Akt signalling pathway.
IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.
ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
Glucose, glutamine, lactic acid and α‑ketoglutarate restore metabolic disturbances and atrophic changes in energy‑deprived muscle cells.
Targeting TRPML3 inhibits proliferation and invasion, and enhances doxorubicin sensitivity by disrupting lysosomal acidification and mitochondrial function in triple-negative breast cancer.
Enhancement of Energy Metabolism in Skeletal Myocytes Protects Against Age-Related Sarcopenia.

PLoS Biol. 2024 Aug;22(8): e3002754

To transfer mitochondria or not to transfer mitochondria: ADP does the trick.

Jaromir Novak, Jiri Neuzil.

Horizontal mitochondrial transfer (HMT) has emerged as a novel phenomenon in cell biology, but it is unclear how this process of intercellular movement of mitochondria is regulated. A new study in PLOS Biology reports that ADP released by stressed cells is a signal that triggers HMT.

DOI: https://doi.org/10.1371/journal.pbio.3002754
J Cell Sci. 2025 May 01. pii: jcs263895. [Epub ahead of print]138(9):

Mitochondria-membranous organelle contacts at a glance.

Antigoni Diokmetzidou, Luca Scorrano.

  Mitochondrial contact sites are specialized interfaces where mitochondria physically interact with other organelles. Stabilized by molecular tethers and defined by unique proteomic and lipidomic profiles, these sites enable direct interorganellar communication and functional coordination, playing crucial roles in cellular physiology and homeostasis. Recent advances have expanded our knowledge of contact site-resident proteins, illuminated the dynamic and adaptive nature of these interfaces, and clarified their contribution to pathophysiology. In this Cell Science at a Glance article and the accompanying poster, we summarize the mitochondrial contacts that have been characterized in mammals, the molecular mechanisms underlying their formation, and their principal functions.

Keywords:  Contact sites; Mitochondria; Organelles

DOI:  https://doi.org/10.1242/jcs.263895
Int J Biol Macromol. 2025 May 10. pii: S0141-8130(25)04679-3. [Epub ahead of print]312 144127

MICU1 is the nexus for CaV3.3 regulation of mitochondrial calcium, redox balance and chondrocyte viability.

Yumengfei Huang, Lucky Laras Prastyaningrum, Xin Wang, Fa Xu, Zonghan Wang, Zhi Wang, Xin Tan, Gang Dai, Guangxing Chen, Xiaoyuan Gong, Liu Yang.

  Voltage-gated calcium channels are emerging regulators of cellular homeostasis, but their molecular interplay with mitochondrial bioenergetics in chondrocytes remains poorly characterized. This study elucidates how the T-type calcium channel CaV3.3 governs mitochondrial calcium-redox coupling through structural interactions with MICU1, the regulatory subunit of the mitochondrial calcium uniporter (MCU) complex. The absence of the CaV3.3 precipitated mitochondrial ultrastructural disorganization characterized, coupled with MICU1 downregulation and consequent loss of MCU gating fidelity. Through integrated transcriptomic-proteomic profiling and live-cell imaging, we demonstrate that CaV3.3 deficiency induces pathological mitochondrial calcium influx, triggering Reactive oxygen species (ROS) overproduction and bioenergetic collapse, these metabolic derangements activated intrinsic apoptosis. Notably, lentiviral overexpression of MICU1 in CaV3.3 knockout cells restored the mitochondrial calcium set point and inhibited ROS burst, while rescued cell proliferation and inhibited apoptosis execution. Our findings establish CaV3.3 as a redox rheostat coordinating MICU1-mediated mitochondrial calcium buffering, with direct implications for cartilage matrix maintenance and osteoarthritis therapy targeting calcium-handling macromolecules.

Keywords:  MICU1; Mitochondrial calcium homeostasis; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144127
EXCLI J. 2025 ;24 433-449

Using novel oxidative phosphorylation inhibitors to attenuate drug resistance in human gliomas.

Chia-Kuang Tsai, Chin-Yu Lin, Yung-Lung Chang, Fu-Chi Yang, Chung-Hsing Chou, Yu-Chian Huang, Dueng-Yuan Hueng.

  Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor prognosis, worsened by resistance to temozolomide (TMZ). TMZ-induced DNA damage is counteracted by the repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT), promoting tumor recurrence. Targeting oxidative phosphorylation (OXPHOS), essential for cellular energy production, offers a potential therapeutic strategy to overcome TMZ resistance and improve GBM treatment outcomes. Gboxin, a small-molecule drug, selectively inhibits OXPHOS by targeting complex V, with minimal toxicity to normal cells. It accumulates in the mitochondria of GBM cells, exploiting their high membrane potential and pH, thereby inhibiting cell proliferation. This study evaluates Gboxin's efficacy in TMZ-resistant (TMZ-R) GBM. Results show that Gboxin suppresses the growth of both TMZ-sensitive and TMZ-R GBM cells by inhibiting proliferation, inducing apoptosis, and reducing OXPHOS activity. These findings were confirmed in an in vivo model, highlighting Gboxin as a promising therapeutic for both TMZ-sensitive and TMZ-R GBM. See also the graphical abstract(Fig. 1).

Keywords:  Gboxin; PLK2; glioblastoma; oxidative phosphorylation capacity

DOI:  https://doi.org/10.17179/excli2025-8193
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2415268122

Split genetically encoded calcium indicators for interorganellar junctions.

Shunit Olszakier, Wessal Hussein, Ronit Heinrich, Michael Andreyanov, Achinoam Blau, Yara Otor, Jackie Schiller, Shai Kellner, Shai Berlin.

  Genetically encoded calcium indicators (GECIs) have revolutionized the study of cellular calcium signaling, offering powerful tools for real-time optical monitoring of calcium dynamics. Although contemporary GECIs can be targeted to various organelles, there are no means to obtain active and functional GECIs exclusively at interorganellar junctions. To address this gap, we have developed a toolbox of split versions of green and red GECIs designed to reassemble only when the two "halves" come into proximity. We developed split probes to investigate interorganellar connectivity and activity between mitochondria and the ER (via split-MEGIC) or between the plasma membrane and the ER (via split-sf-MEMBER). We employ the various split-sensors to image neural Ca2+ activity in vitro and in vivo and, in the process, identify Mito-ER junctions and calcium activity within individual dendritic spines by use of split-MEGIC.

Keywords:  calcium; neurons; organelle; spine; split

DOI:  https://doi.org/10.1073/pnas.2415268122
Mol Cancer Res. 2025 May 16.

Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.

Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers.

TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine dependency of mitochondrial respiration following glucose withdrawal. Here, we investigate how TRAP1 deletion impacts glucose metabolism and the mechanisms enabling glutamine retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although glucose oxidation remains functional, TRAP1 KO reduces overall glucose uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased glutamine retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces glutamine-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest xCT is regulated post-translationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases glucose uptake while preserving its metabolic fate, promoting glutamine conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis. Implications: These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated glutamine conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0194
Front Pharmacol. 2025 ;16 1532579

Saikosaponin A induces cellular senescence in triple-negative breast cancer by inhibiting the PI3K/Akt signalling pathway.

Yingchao Wu, Liushan Chen, Dajin Pi, Jiaqi Cui, Yuqi Liang, Peng Wu, Mingzi Ouyang, Qian Zuo.

   Background: Breast cancer has now become the most prevalent cancer worldwide. Existing therapeutic agents are generally accompanied by significant side effects. Here, we highlight Saikosaponin A (SSA), a promising natural metabolite characterized by low toxicity, demonstrating significant efficacy against breast cancer through the induction of cellular senescence.
Methods: The antitumor property of SSA was determined via MTT colorimetric assay, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, colony formation, and propidium iodide (PI) staining in vitro, as well as xenograft in vivo model. A network approach was used to predict potential targets of SSA reevant for a potential anti-tumor effect and verified through senescence-associated β-galactosidase (SA-β-gal), flow-cytometry analysis, RT-PCR, Western blotting, and immuno-histochemistry assay.
Results: SSA significantly suppressed proliferation and triggered cell cycle arrest of SUM159PT and MDA-MB-231 cells. Revealed by network analysis, cellular senescence, and phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway were implemented in the anti-tumor effects of SSA. SSA-stimulated senescence was associated with increased ROS production, distinct senescence-associated secretory phenotype (SASP), and restricted PI3K/Akt signaling, as well as p21 and p53 accumulation. Furthermore, SSA displayed inhibitory effects on tumor growth with minimal toxicity in animal studies, accompanied by activated biomarkers of cellular senescence and decreased expression of p-Akt and p-PI3K.
Conclusion: Taken together, based on the preliminary results of network analysis and further experimental validation, this study revealed that SSA significantly induced cell cycle arrest and senescence, and the inhibition of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process.

Keywords:  PI3K/Akt signaling pathway; breast cancer; cellular senescence; network analysis; saikosaponin a

DOI:  https://doi.org/10.3389/fphar.2025.1532579
Cell Rep. 2025 May 09. pii: S2211-1247(25)00465-6. [Epub ahead of print]44(5): 115694

IRE1α promotes phagosomal calcium flux to enhance macrophage fungicidal activity.

Michael J McFadden, Mack B Reynolds, Britton C Michmerhuizen, Einar B Ólafsson, Sofia M Marshall, Faith Anderson Davis, Tracey L Schultz, Takao Iwawaki, Jonathan Z Sexton, Mary X D O'Riordan, Teresa R O'Meara.

  The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity and microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent roles are less well understood, and its functions during fungal infection are still emerging. We demonstrate that Candida albicans activates macrophage IRE1α via C-type lectin receptor signaling independent of protein misfolding, suggesting non-canonical activation. IRE1α enhances macrophage fungicidal activity by promoting phagosome maturation, which is crucial for containing C. albicans hyphae. IRE1α facilitates early phagosomal calcium flux post-phagocytosis, which is required for phagolysosomal fusion. In macrophages lacking the IRE1α endoribonuclease domain, defective calcium flux correlates with fewer ER-early endosome contact sites, suggesting a homeostatic role for IRE1α-promoting membrane contact sites. Overall, our findings illustrate non-canonical IRE1α activation during infection and a function for IRE1α in supporting organelle contact sites to safeguard against rapidly growing microbes.

Keywords:  CP: Immunology; CP: Microbiology; Candida albicans; IRE1α; calcium; fungal infection; innate immunity; phagosome

DOI:  https://doi.org/10.1016/j.celrep.2025.115694
Nat Cell Biol. 2025 May;27(5): 847-862

ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.

Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Yan Jin, Haiwei Gu, Chia-Yang Li, Hui-Kuan Lin.

MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1-MPC2 to maintain the integrity and oligomerization of MPC1-MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.

DOI: https://doi.org/10.1038/s41556-025-01651-8
Mol Med Rep. 2025 Jul;pii: 197. [Epub ahead of print]32(1):

Glucose, glutamine, lactic acid and α‑ketoglutarate restore metabolic disturbances and atrophic changes in energy‑deprived muscle cells.

Miu Ikeda, Moe Matsumoto, Miki Tamura, Masaki Kobayashi, Kaoruko Iida.

  Skeletal muscle atrophy is often triggered by catabolic conditions such as fasting, malnutrition and chronic diseases; however, the efficacy of nutritional supplementation in maintaining muscle mass and preventing muscle atrophy remains controversial. The present study aimed to compare the inhibitory effects of various nutritional substrates on starvation‑induced catabolic changes and muscle cell atrophy. C2C12 muscle cells were starved for up to 24 h in medium lacking serum and main nutrients (glucose, glutamine and pyruvate). To assess the effects of exogenous substrates, the cells were incubated in starvation medium and individually supplemented with each of the following nutrients: Glucose, amino acids, fatty acids, lactate or ketone bodies. The expression of each gene and protein was analyzed by reverse transcription‑quantitative PCR and western blotting, respectively. Mitochondrial activity was determined by MTT assay and cell morphology was observed by immunofluorescence staining. The results revealed that starvation for >3 h suppressed mitochondrial activity, and after 5 h of starvation, the expression levels of several metabolic genes were increased; however, the levels of most, with the exception of Scot and Cpt‑1b, were suppressed after 24 h. Protein degradation and a decrease in protein synthesis were observed after 5 h of starvation, followed by autophagy with morphological atrophy at 24 h. Supplementation with specific substrates, with the exception of leucine, such as glucose, glutamine, lactic acid or α‑ketoglutarate, attenuated the suppression of mitochondrial activity, and altered gene expression, protein degradation and myotube atrophy in starved myotubes. Furthermore, the decrease in intracellular ATP production after 24 h of starvation was reversed by restoring glycolysis in glucose‑treated cells, and via an increase in mitochondrial respiration in cells treated with glutamine, lactic acid or α‑ketoglutarate. In conclusion, increasing the availability of glucose, glutamine, lactic acid or α‑ketoglutarate may be beneficial for countering muscle atrophy associated with inadequate nutrient intake.

Keywords:  atrophy; metabolism; muscle cells; nutrient substrates; starvation

DOI:  https://doi.org/10.3892/mmr.2025.13562
Biochim Biophys Acta Mol Cell Res. 2025 May 08. pii: S0167-4889(25)00084-9. [Epub ahead of print] 119979

Targeting TRPML3 inhibits proliferation and invasion, and enhances doxorubicin sensitivity by disrupting lysosomal acidification and mitochondrial function in triple-negative breast cancer.

Gabriela Maria De Abreu Gomes, Mengnan Xu, Alia Kazim Rizvi Syeda, Renee Raudonis, Shekoufeh Almasi, Vishnu Vijay Vijayan, Shashi Gujar, Xianping Dong, Zhenyu Cheng, Thomas Pulinilkunnil, Yassine El Hiani.

  TNBC remains the most aggressive and therapy-resistant type of breast cancer, for which efficient targeted therapies have not been developed yet. Here, we identified TRPML3 (ML3) as a potential therapeutic target in TNBC. Our data showed that ML3 is significantly upregulated in TNBC cells compared with nontumorigenic control cells. ML3 knockdown (KD) imapirs TNBC cell proliferation by inducing cell cycle arrest and caspase-dependent apoptosis. ML3 KD also inhibits TNBC cell migration and invasion. Mechanistically, ML3 KD reduces lysosomal number and enhances lysosomal acidification, which in turn activates mTORC1, thereby inhibiting autophagy initiation and flux. This disruption negatively impacts mitochondrial function, as evidenced by reduced ATP production, increased ROS and NO production, and mitochondrial fragmentation. Importantly, ML3 KD enhances TNBC cell sensitivity to doxorubicin and paclitaxel. The finding suggests that targeting ML3 disrupt lysosomal and mitochondrial homeostasis and enhance chemosensitivity, presenting ML3 as a potential therapeutic vulnerability in TNBC enhancing chemosensitivity.

Keywords:  Autophagy; Breast cancer; Lysosomes; Mitochondria; TNBC; TRPML3

DOI:  https://doi.org/10.1016/j.bbamcr.2025.119979
J Cell Mol Med. 2025 May;29(9): e70588

Enhancement of Energy Metabolism in Skeletal Myocytes Protects Against Age-Related Sarcopenia.

Andrey Y Vinokurov, Pavel A Bazhenov, Marina Y Pogonyalova, Evgenia S Seryogina, Ekaterina A Vetrova, Larisa Andreeva, Andrey Y Abramov, Plamena R Angelova.

  Skeletal muscles constantly consume energy, and this consumption level increases correspondingly to the levels of physical activity. Mitochondrial energy metabolism requires constant supplementation with oxygen and substrates for ATP production. Limitation of the mitochondrial substrate supply leads to energy deprivation, which may be followed by sarcopenia and weight loss. Activation of mitochondrial energy metabolism can also stimulate the production of reactive oxygen species and oxidative stress. Here, we studied the effect of various mitochondrial substrates on the energy metabolism of primary skeletal myotubes and how it affects redox balance. We found that as individual components-glutamate, succinate, nicotinamide (NAM) as well as in combination-dicholine succinate (DISU) plus NAM, they increase mitochondrial membrane potential, alter NADH and FAD redox indices, which leads to an increased energy capacity of the skeletal myotubes. Changes in mitochondrial metabolism increased ROS production in mitochondria and cytosol but induced only a minor decrease in the level of the endogenous antioxidant reduced glutathione. Supplementation of young and aged rats with DISU + NAM through the drinking water for 7 days significantly increased myotube diameter in both age groups. Thus, provision of the myotubes with mitochondrial metabolism substrates activates energy metabolism and increases energy capacity but has no effect on oxidative stress. Moreover, it increases myotubes' diameters in young and aged rodent sarcopenia models in vivo.

Keywords:  energy metabolism; glutathione; mitochondria; myotubes; reactive oxygen species; sarcopenia

DOI:  https://doi.org/10.1111/jcmm.70588