bims-mithem 2025-07-27 papers

bims-mithem

Biomed News

on Mitochondria in Hematopoiesis

Issue of 2025–07–27
thirteen papers selected by
Tim van Tienhoven, Erasmus Medical Center

Modulation of Redox Metabolism, CD147, and CD47 Expression with the Maturation of Hematopoietic Stem Cells in Bone Marrow.
Clonal hematopoiesis in myeloid malignancies and solid tumors.
Programmed cell death regulates hematopoietic cell homeostasis under radiation conditions.
Mitochondria as Regulators of Nonapoptotic Cell Death in Cancer.
ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.
Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
Tunneling nanotubes between glioblastoma cells and T cells and hijack of mitochondria.
Clonal haematopoiesis to clonal cytopenias: unravelling disease evolution over time.
Mitochondrial metabolism reprogramming-mediated cardiomyocyte senescence involved in arsenic stress-evoked heart failure.
Determination of Mitochondrial Morphology in Live Cells Using Confocal Microscopy.
Metabolic Dysregulation in Parkinson's Disease: Non-Oxidative Phosphorylation and Its Role in Brain Energy Metabolism.
Erythropoietin (EPO) Alleviates Chronic Stress-Induced Depression by Modulating SIRT1-Mediated Mitochondrial Function.
The SARS-CoV-2 main protease causes mitochondrial dysfunction in a yeast model.

Indian J Hematol Blood Transfus. 2025 Jul;41(3): 629-639

Modulation of Redox Metabolism, CD147, and CD47 Expression with the Maturation of Hematopoietic Stem Cells in Bone Marrow.

Nitin Bhardwaj, Ashutosh Singh, Ram Babu, Mohammad Z Ahmed.

  Haematopoiesis is a continuous process that involves the commitment of pluripotent hematopoietic stem cells (HSCs) into multipotent progenitors (MPPs) and differentiation into functional blood cells. The current study aimed to investigate the prevalence of various HSC progenitors in the bone marrow (BM) as well as alterations in the production of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and surface expression level of basigin (CD147) and integrin-associated protein (CD47) receptors on various HSC lineages. Different HSC progenitors (GMP, CMP, MEP, MPP, ST-HSC, and LT-HSC) cells were recognised based on the surface expression of CD117/Sca-1/CD16/32/CD34 and CD117/Sca-1/CD135/CD34 receptors by flow cytometric analysis. Our results suggest that among Sca-1- cells, the proportion of MPP cells was significantly higher than STHSC and LTHSC. Among Sca1+ cells, the GMP cells were more prevalent, approximately three times more than CMP, while MEP cells were least in proportion. The HSC maturation leads to a significant change in metabolism and surface receptor expression. The LTHSC and STHSC have similar ROS levels, but it was 7 times greater on MPP. The ROS level also increased from CMP to GMP transition (34% increase), but it was reduced significantly on MEP. MMP was significantly higher on MPP and GMP as compared to LTHSC and STHSC, and CMP and MEP, respectively. The surface expression of CD147 was increased significantly from LTHSC/STHSC to MPP and CMP to GMP transition. CD47 receptor expression was also increased during the maturation of HSC. It was almost similar on LTHSC and STHSC but increased on MPP. Similarly, CMP and MEP cells have equivalent CD47 expression but are upregulated on GMP. Overall, HSC maturation involves a series of metabolic changes, which regulate HSC differentiation into progenitor cells in the BM.

Keywords:  Bone marrow; CD147; CD47; Hematopoietic stem cells; Mitochondria; Reactive oxygen species

DOI:  https://doi.org/10.1007/s12288-024-01911-x
Nat Cancer. 2025 Jul 18.

Clonal hematopoiesis in myeloid malignancies and solid tumors.

Xiurong Cai, Robert L Bowman, Jennifer J Trowbridge.

Clonal hematopoiesis (CH) results from clonal expansion of hematopoietic stem cells. In specific contexts, CH is linked with an increased risk of blood cancers and mortality in individuals with solid tumors. To understand the mechanisms and clinical relevance of this association, it is crucial to explore the reciprocal relationship between CH and cancer. Here, we provide an updated summary of the mechanisms known to drive CH in blood cancers and solid tumors. In addition, we review proposed strategies to intercept CH and examine their impact on solid tumor-directed therapies, including immunostimulatory therapies.

DOI: https://doi.org/10.1038/s43018-025-01014-0
Stem Cell Res Ther. 2025 Jul 21. 16(1): 390

Programmed cell death regulates hematopoietic cell homeostasis under radiation conditions.

Manling Shu, Jinfu Zhang, Yuhong Peng, Zhengyang Li, Xin Shu, Jie Wang, Huihong Zeng, Lijian Shao.

   BACKGROUND: It is well-known that hematopoietic cells are sensitive to irradiation exposure. Apoptosis, necroptosis, pyroptosis and ferroptosis might contribute to irradiation-induced hematopoietic injury. However, it is uncertain whether different hematopoietic cells apply specific cell death pathways under irradiation exposure.
METHODS: We investigated the role of different programmed cell death pathways in irradiation-induced hematopoietic cell injury. In order to study the acute and long-term effects of ionizing radiation on hematopoietic system, we established injury models of mice at different time points after irradiation and measured the proportion of hematopoietic stem progenitor cells by flow cytometry. The pattern of programmed cell death involved in radiation-induced hematopoietic cell injury was identified through the analysis of different populations of hematopoietic cells in the bone marrow by immunomagnetic bead sorting combined with qRT-PCR and flow cytometry. The role of pyroptosis in radiation injury of hematopoietic stem cells was further studied by Caspase-1 inhibitor VX-765 application. In vivo spleen colony formation, competitive bone marrow transplantation and secondary transplantation were used to verify the protective effect of inhibiting Caspase-1 on hematopoietic stem cells damaged by radiation. RNA sequencing (RNA-Seq) using Lin-c-Kit+ cell populations revealed the mechanism by which inhibition of Caspase-1 mitigates post-irradiation hematopoietic stem cell damage.
RESULTS: A single exposure to whole-body ionizing radiation of 3 Gy causes acute bone marrow injury and long-term myelosuppression, resulting in hematopoietic imbalances and a bias toward myeloid differentiation. Ionizing radiation induced bone marrow B cell apoptosis and necroptosis, bone marrow T cell apoptosis. Various programmed cell death modes were involved in radiation injury of hematopoietic stem cells. Inhibition of Caspase-1 by VX-765 accelerated the recovery of hematopoietic stem cells after radiation. It is worth noting that inhibition of Caspase-1 promotes the proliferation and differentiation of hematopoietic stem cells after ionizing radiation. VX-765 treatment under ionizing radiation stress increased numbers of spleen colony formation, ability of long-term hematopoietic reconstitution in vivo and self-renewal. VX-765 alleviates post-irradiation hematopoietic stem cell injury by inhibiting pyroptosis, apoptosis and necroptosis.
CONCLUSIONS: These data suggest that multiple programmed cell death pathways are involved in radiation-induced damage to hematopoietic cells. Inhibiting Caspase-1 activity can be used as a strategy for protecting against radiation-induced injury to hematopoietic stem cells.

Keywords:  Apoptosis; Hematopoietic cells; Ionizing radiation; Necroptosis; Pyroptosis

DOI:  https://doi.org/10.1186/s13287-025-04502-3
MedComm (2020). 2025 Aug;6(8): e70244

Mitochondria as Regulators of Nonapoptotic Cell Death in Cancer.

Saloni Malla, Rabin Neupane, Saloni Sood, Noor Hussein, Mariam Abou-Dahech, David Terrero, Charles R Ashby, R Jayachandra Babu, Amit K Tiwari.

  Mitochondria are involved in cell survival and metabolic processes including adenosine triphosphate production, heme biosynthesis, reactive oxygen species, and iron and calcium homeostasis. Although mitochondria are well known to contribute to apoptosis, a growing body of evidence indicates that mitochondria modulate nonapoptotic cell death (NACD) mechanisms, including autophagy, necroptosis, ferroptosis, paraptosis, pyroptosis, parthanatosis, and cuproptosis. These NACD pathways differ in molecular triggers, morphological characteristics, and immunological consequences, but they all involve mitochondria. For example, mitochondrial ROS and lipid peroxidation play a role in ferroptosis, whereas mitochondrial depolarization and the release of apoptosis inducing factor are paramount to parthanatosis. Mitochondrial swelling is a hallmark of paraptosis, whereas mitochondrial disruption is associated with pyroptosis. Autophagy, though primarily a survival mechanism, is also regulated by mitochondrial dynamics in cancer cells. In cuproptosis, mitochondrial protein aggregates when iron-sulfur cluster proteins are disrupted, resulting in copper-dependent cell death. There are many factors that influence NACD, including mitochondrial membrane potential, bioenergetics, calcium flux, metabolites, and interactions with the endoplasmic reticulum. The review comprehensively summarizes our understanding of mitochondrial and NACD interactions, particularly in cells resistant to classical apoptosis agents. Therapeutic vulnerabilities associated with mitochondria-mediated NACD could lead to next-generation therapies.

Keywords:  autophagy; cancer; ferroptosis; mitochondria; necroptosis; nonapoptotic cell death

DOI:  https://doi.org/10.1002/mco2.70244
Metabolites. 2025 Jul 07. pii: 461. [Epub ahead of print]15(7):

ATP Supply from Cytosol to Mitochondria Is an Additional Role of Aerobic Glycolysis to Prevent Programmed Cell Death by Maintenance of Mitochondrial Membrane Potential.

Akane Sawai, Takeo Taniguchi, Kohsuke Noguchi, Taisuke Seike, Nobuyuki Okahashi, Masak Takaine, Fumio Matsuda.

  Eukaryotic cells generate ATP primarily via oxidative and substrate-level phosphorylation. Despite the superior efficiency of oxidative phosphorylation, eukaryotic cells often use both pathways as aerobic glycolysis, even in the presence of oxygen. However, its role in cell survival remains poorly understood. Objectives: In this study, aerobic glycolysis was compared between the Warburg effect in breast cancer cells (MCF7) and the Crabtree effect in a laboratory strain of Saccharomyces cerevisiae (S288C). Methods: The metabolic adaptations of MCF7 and S288C cells were compared following treatment with electron transport chain inhibitors, including FCCP, antimycin A, and oligomycin. Results: MCF7 and S288C cells exhibited strikingly similar metabolic rewiring toward substrate-level phosphorylation upon inhibitor treatment, suggesting that mitochondrial oxidative phosphorylation and cytosolic substrate-level phosphorylation communicate through a common mechanism. Measurement of mitochondrial membrane potential (MMP) and ATP concentrations further indicated that cytosolic ATP was transported into the mitochondria under conditions of reduced electron transport chain activity. This ATP was likely utilized in the reverse mode of H+/ATPase to maintain MMP, which contributed to the avoidance of programmed cell death. Conclusions: These results suggest that the ATP supply to mitochondria plays a conserved role in aerobic glycolysis in yeast and mammalian cancer cells. This mechanism likely contributes to cell survival under conditions of fluctuating oxygen availability.

Keywords:  Saccharomyces cerevisiae; aerobic glycolysis; breast cancer cells; metabolic rewiring; mitochondrial membrane potential; programmed cell death; reverse mode of H+/ATPase

DOI:  https://doi.org/10.3390/metabo15070461
Res Sq. 2025 Jul 15. pii: rs.3.rs-7042684. [Epub ahead of print]

Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.

Tim Heden, Melina Mancini, Cameron McCall, Robert Noland, Wagner Dontas.

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

DOI: https://doi.org/10.21203/rs.3.rs-7042684/v1
J Neurooncol. 2025 Jul 21.

Tunneling nanotubes between glioblastoma cells and T cells and hijack of mitochondria.

Yanamandra Venkataratnam, Victor Mukherjee, Nikhil Rai, Mahesh Mahalingaswamy, Diksha Shandilya, Subhas Konar, Nandeesh Bevinahalli Nanjegowda, Girish Waghmare, Nandakumar Dalavaikodihalli Nanjaiah.

   PURPOSE: Glioblastoma is a highly aggressive and invasive brain tumor that can interact dynamically with its surrounding tumor microenvironment, including resident and infiltrating-immune cells. These interactions largely govern glioblastoma progression and resistance to therapy. Glioblastoma cells can actively modulate immune cell functions, either by inhibiting immune responses or reprogramming immune cells. This study explores the dynamic interaction between glioblastoma cells and T cells.
METHODS: The connections between glioblastoma cells and T cells were analyzed by immunohistochemistry, immunofluorescence and scanning electron microscopy. Inhibition of tunneling nanotubes (TNTs) between glioblastoma cells and T cells was performed using carbenoxolone. Fluorogenic probes were used for mitochondrial membrane potential and reactive oxygen species (ROS) in mitochondria, glioblastoma cells and T cells after co-culture. Viability and LAG-3 levels were analyzed in T cells.
RESULTS: Glioblastoma cells show connections between themselves and forms physical connections with T cells through TNTs. Glioblastoma cells hijack mitochondria from T cells through these connections and effect was reversed on using carbenoxolone. Glioblastoma cells show increased mitochondrial membrane potential and decreased mitochondrial ROS after co-culture, while ROS was increased in glioblastoma cells and decreased in T cells.
CONCLUSION: We show for the first time that glioblastoma cells and T cells physically connect through TNTs. Most importantly, glioblastoma cells hijack the mitochondria of T cells for its own advantage. By focusing on these complex tumor-immune cell interactions, this study aims to uncover a novel mode of physical communication in glioblastoma microenvironment.

Keywords:  Glioblastoma; Immune cells; Mitochondrial transport; Tumor microenvironment; Tunneling nanotubes

DOI:  https://doi.org/10.1007/s11060-025-05150-6
Lancet Haematol. 2025 Jul 17. pii: S2352-3026(25)00137-1. [Epub ahead of print]

Clonal haematopoiesis to clonal cytopenias: unravelling disease evolution over time.

Kristina Kirschner, Yael Kusne, Catherine Cargo, Mrinal M Patnaik.

Clonal haematopoiesis refers to the presence of somatic mutations in haematopoietic stem and progenitor cells, accompanied by the expansion of high-fitness clones over time. Age-related clonal haematopoiesis arises from ageing-related DNA damage and is associated with haematological neoplasms and coronary artery disease. Genotoxic therapies can promote the selection of somatic mutations, leading to therapy-related clonal haematopoiesis. Clonal haematopoiesis in acquired or inherited bone marrow failure syndromes and germline predispositions leads to clonal expansion, where fitness constraints on haematopoietic stem cells drive mutation acquisition. When clonal haematopoiesis occurs in the context of persistent unexplained cytopenias, with somatic mutations driving haematopoietic dysfunction, it is referred to as clonal cytopenias of undetermined significance (CCUS). CCUS is a precursor to myeloid neoplasms, with variable progression rates. In this Review, we summarise the current state of knowledge, offering critical insights into the molecular evolution of, and diagnostics and risk assessment for clonal haematopoiesis and CCUS. We highlight the interplay between ageing and environmental factors in the progression to haematological neoplasms and discuss challenges for risk stratification and disease monitoring.

DOI: https://doi.org/10.1016/S2352-3026(25)00137-1
Environ Int. 2025 Jul 14. pii: S0160-4120(25)00437-4. [Epub ahead of print]202 109686

Mitochondrial metabolism reprogramming-mediated cardiomyocyte senescence involved in arsenic stress-evoked heart failure.

Yán Wāng, Yapeng Han, De-Xiang Xu.

  Chronic exposure to environmental inorganic arsenic is associated with cardiotoxicity, but the underlying mechanisms remain poorly understood. This study investigated how arsenite disrupts mitochondrial metabolism, focusing on the tricarboxylic acid (TCA) cycle, and its role in cardiomyocyte senescence and dysfunction. Proteomics and metabolomics analysis revealed that environmental arsenic exposure altered mitochondrial electron transport chain (ETC) proteins and impaired key enzymes in the TCA cycle, including citrate synthase and succinate dehydrogenase. In vivo drinking exposure to environmental arsenite for six months significantly downregulated mitochondrial metabolic enzymes, leading to disruptions in energy metabolism and cardiac aging. In vitro experiments using AC16 human cardiomyocytes confirmed that environmental arsenite exposure induced early senescence, characterized by increased expression of the aging-related marker CDKN1A and the cardiac injury marker NPPB. Even sub-cytotoxic doses of arsenite impaired mitochondrial TCA cycle function before inducing senescence and injury. Dietary supplementation with nicotinamide mononucleotide (NMN) in vivo and administration with NMN in vitro mitigated cardiomyocyte senescence-associated secretory phenotype and heart failure, suggesting that cardiac aging plays a central role in arsenic-induced functional impairment. Treatment with the mitochondrial antioxidant Mito-TEMPO alleviated these effects, restoring TCA cycle enzyme activity, reducing senescence, and improving cardiomyocyte function across multiple cell generations. These findings suggest that mitochondrial metabolic reprogramming plays a central role in environmental stressor arsenite-induced cardiomyocyte aging and identify mitochondrial metabolism as a potential target to mitigate arsenic-induced cardiac dysfunction.

Keywords:  Cardiac hypertrophy; Cell senescence; Environmental stress; Heart failure; Nicotinamide mononucleotide

DOI:  https://doi.org/10.1016/j.envint.2025.109686
J Vis Exp. 2025 Jul 03.

Determination of Mitochondrial Morphology in Live Cells Using Confocal Microscopy.

Manna Lin, Jiakang Wang, Zihong Xian, Chunyuan Zeng, Jiangping Xu.

The dynamic balance of mitochondrial fusion and fission directly contributes to mitochondrial homeostasis, which influences numerous cellular functions in addition to adenosine triphosphate (ATP) homeostasis. Therefore, assessing mitochondrial morphology under stress conditions is essential for mechanistic research. This study describes a detailed protocol for analyzing mitochondrial morphology, encompassing the preparation of a MitoTracker solution, staining of mitochondria, optimization of imaging parameters, and detection of morphological features. MitoTrackers are commonly used, cost-effective mitochondrion-specific dyes. However, some changes in mitochondrial morphology may occur owing to inappropriate handling, which can be unperceivable and fail to reflect the true state of mitochondria. Therefore, it is necessary to understand how to analyze changes in mitochondrial morphology using MitoTrackers. The protocol utilized SH-SY5Y cells stimulated with 1-methyl-4-phenylpyridinium iodide (MPP+) to illustrate the protocol of mitochondrial morphological analysis. Compared with control cells, MPP+-stimulated cells exhibited smaller and more fragmented mitochondria, with morphological parameters indicating decreased mitochondrial footprint. These results suggest that MitoTracker staining is an effective and feasible method for mitochondrial morphological analysis that (with minor modifications) can be applied to study various conditions.

DOI: https://doi.org/10.3791/68167
Aging Dis. 2025 Jul 06.

Metabolic Dysregulation in Parkinson's Disease: Non-Oxidative Phosphorylation and Its Role in Brain Energy Metabolism.

Marta Pokotylo, Norbert Brüggemann, Jannik Prasuhn.

Parkinson's disease (PD) is a progressive neurodegenerative condition affecting around 1-2% of the population over the age of 60. The lack of disease-modifying therapies highlights the need for insights into the etiology and pathogenesis of PD. Mitochondrial dysfunction is recognized to be a significant contributor to disease pathogenesis, resulting in bioenergetic deficits and subsequent neurodegeneration. Research indicates that changes in non-oxidative phosphorylation (non-OXPHOS) metabolism in PD may serve as an adaptive response to mitochondrial dysfunction, compensating for energetic failure and alleviating disease progression. This review explores mitochondrial dysfunction-driven alterations in non-OXPHOS metabolic pathways, such as glycolysis and the tricarboxylic acid cycle, emphasizing their role in maintaining energy metabolism and their dual contribution to neuroprotection and disease progression. Advances in neuroimaging techniques are also discussed, particularly their role in visualizing metabolic changes in vivo and their potential utility in identifying non-OXPHOS metabolism as a biomarker of mitochondrial dysfunction. By enhancing our understanding of the complex interplay between metabolic pathways in PD, this review underscores the importance of personalized therapeutic approaches that consider individual metabolic variations. Ultimately, these insights aim to pave the way for improved diagnostic utility and personalized treatment strategies that address the metabolic and mitochondrial dysfunctions underlying PD pathogenesis.

DOI: https://doi.org/10.14336/AD.2025.0619
J Neuroimmune Pharmacol. 2025 Jul 21. 20(1): 73

Erythropoietin (EPO) Alleviates Chronic Stress-Induced Depression by Modulating SIRT1-Mediated Mitochondrial Function.

Yanhua Luo, Tahir Ali, Yue Hu, Qichao Gong, Chengyou Zheng, Ling Li, Shupeng Li, Liangliang Hao.

  Mitochondrial dysfunction is a hallmark of many psychiatric disorders, and SIRT1 signaling plays a critical role in regulating mitochondrial dynamics, function, and autophagy. This study investigated the interplays between erythropoietin (EPO), mitochondrial protection, and SIRT1 signaling in depression. Chronic restraint stress (CRS)- induced depression mouse model and CORT-treated HT22 cells were employed, which were subsequently treated with EPO. CRS mice exhibited depressive-like behaviors, which were alleviated by EPO treatment, as evidenced by decreased immobility and increased sucrose preference. EPO also enhanced mitochondrial function by stimulating mitophagy and improving mitochondrial homeostasis, as indicated by elevated ATP levels, reduced nitric oxide, and restored expression of mitochondrial-related genes in both the hippocampus of CRS mice and CORT-treated HT22 cells. Additionally, EPO restored suppressed SIRT1 expression, promoted dendritic spine density and synaptic gene expression in the hippocampus, increased p-STAT5 phosphorylation, and increased NAMPT expression and NAD + levels. Notably, pharmacological inhibition of SIRT1 via EX-527 counteracted EPO effects, exacerbating depressive symptoms and mitochondrial homeostasis. Furthermore, EX-527 treatment decreased ATP levels and mitochondrial DNA copy numbers in CRS + EPO-treated mice and reduced ATG5 expression. However, EX-527 did not significantly impact BNIP3, Parkin, PINK1, LC3B-II, Ace-FOXO1, or FOXO1 expression. EX-527 exposure significantly increased Ac-LC3B precipitation in the hippocampus of CRS + EPO-treated mice and the COXIV/LAMP1 ratio in the HT22 cells. In summary, these results suggested that EPO antidepressant effects were mediated through SIRT1 regulation, which influenced LC3B deacetylation, improving CRS-induced mitochondrial dysfunction and autophagy impairment.

Keywords:  Depression; Erythropoietin; Mitochondrial dysfunction; SIRT1

DOI:  https://doi.org/10.1007/s11481-025-10233-2
Sci Rep. 2025 Jul 18. 15(1): 26106

The SARS-CoV-2 main protease causes mitochondrial dysfunction in a yeast model.

Wojciech Grabiński, Anna Kicińska, Karolina Funtowicz, Tomasz Skrzypczak, Andonis Karachitos.

Saccharomyces cerevisiae has proven to be an invaluable model organism for studying mitochondrial function owing to its genetic tractability and the high conservation of mitochondrial processes among eukaryotes, including humans. Yeasts are easy to culture and manipulate genetically, which allows rapid generation of mutant strains and detailed dissection of mitochondrial pathways. In addition, the ability of yeasts to survive without functional mitochondria allows the study of mutations that are lethal to organisms that are dependent on aerobic metabolism. Taking advantage of these benefits, we investigated the toxicity of SARS-CoV-2 main protease (Mpro) expression in yeast under conditions that enforce mitochondria-dependent aerobic metabolism. Our results showed that Mpro expression was highly toxic and significantly impaired yeast growth. Pronounced changes in the morphology and mitochondrial function were observed, indicating that mitochondrial pathways are exceptionally sensitive to Mpro activity. These results provide insights that may be relevant for understanding the effects of Mpro in more complex eukaryotic systems.

DOI: https://doi.org/10.1038/s41598-025-11993-w