bims-scepro 2025-08-03 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–08–03
twelve papers selected by
William Grey, University of York

Mitochondrial metabolism: Critical mechanisms underpinning normal hematopoietic stem cell and acute myeloid leukemia stem cell function.
Lessons in longevity from blood stem cells under protein stress.
Single cell proteomics characterization of bone marrow hematopoiesis with distinct Ras pathway lesions.
Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.
Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases.
Loss of peroxisome function promotes oxidative stress induced hematopoiesis.
Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML.
Membrane Contact Sites in Proteostasis and ER Stress Response.
Human interpretable grammar encodes multicellular systems biology models to democratize virtual cell laboratories.
Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis.
Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML.

Gene. 2025 Jul 25. pii: S0378-1119(25)00474-3. [Epub ahead of print]966 149685

Mitochondrial metabolism: Critical mechanisms underpinning normal hematopoietic stem cell and acute myeloid leukemia stem cell function.

Huasong Yu, Lin Yan.

  AML (Acute myeloid leukemia) is an aggressive cancer of the blood and bone marrow characterized by the excessive proliferation of immature white blood cells, that disrupt normal hematopoiesis. LSCs (Leukemic stem cells) represent a subpopulation of AML cells with stem cell-like properties that drive AML initiation, progression, and relapse by evading conventional therapies and sustaining leukemic growth. Despite advances in understanding AML biology, particularly their metabolic alternations, remain poorly understood. Indeed, recent studies have shown that mitochondrial metabolism plays a pivotal role in the regulation of both normal HSCs (hematopoietic stem cells) and LSCs. In this review, we delve into the mitochondrial metabolic characteristics of normal HSCs to provide comprehensive background knowledge. Subsequently, we thoroughly analyze how the distinctive metabolic features of LSCs, highlighting the impact of these differences on cell function and survival. We also investigate the unique mechanisms of drug resistance in LSCs, explaining how these mechanisms enhance the survival of LSCs in the face of conventional treatments. Finally, we discuss emerging therapeutic strategies targeting the mitochondrial metabolism of LSCs in AML, and we discuss prospective therapeutic strategies and future research directions.

Keywords:  Acute myeloid leukemia; Hematopoietic stem cell; Leukemia stem cell; Metabolism; Mitochondria; Mitochondrial quality control

DOI:  https://doi.org/10.1016/j.gene.2025.149685
Trends Cell Biol. 2025 Jul 29. pii: S0962-8924(25)00151-5. [Epub ahead of print]

Lessons in longevity from blood stem cells under protein stress.

André Catic.

  Blood stem cells are among the body's longest-living cells despite being highly vulnerable to proteotoxic damage, which accelerates their aging. To maintain protein homeostasis (proteostasis), hematopoietic stem cells (HSCs) employ mechanisms such as reduced translation rates, high chaperone activity, autophagy, and selective protein degradation. These strategies mitigate protein misfolding, maintain quiescence, and preserve regenerative potential. Disruptions in proteostasis can lead to the elimination of impaired HSCs through differentiation or apoptosis, ensuring the integrity of the stem cell pool. Due to the systemic impact of the blood on aging and its experimental and clinical accessibility, investigating HSC proteostasis provides insights into longevity and potential therapeutic strategies. This review examines emerging mechanistic links between proteostasis and HSC fate, concluding with unresolved questions and challenges of the current research.

Keywords:  aging; autophagy; hematopoietic stem cells (HSCs); proteasome; protein homeostasis (proteostasis); translation control

DOI:  https://doi.org/10.1016/j.tcb.2025.06.006
Blood Adv. 2025 Jul 30. pii: bloodadvances.2024014411. [Epub ahead of print]

Single cell proteomics characterization of bone marrow hematopoiesis with distinct Ras pathway lesions.

Laila Karra, Anna-Marie Finger, Lauren A Shechtman, Milana Krush, Rita Meng-Yao Huang, Morgan Prinz, Iliana Tennvooren, Kriti Bahl, Lisiena Hysienaj, Paulina Garcia-Gonzalez, Alexis J Combes, Hugo Gonzalez, Rafael Jose Argüello, Mathew H Spitzer, Jeroen P Roose.

Aberrantly elevated Ras signals, triggered by various distinct genetic mutations, are frequent features in myeloid leukemias. Normal hematopoiesis requires perpetual and balanced production of different blood cell lineages by multipotent hematopoietic stem cells (HSC). Stem- and progenitor- cells combine dormancy with proliferative drive and require finely tuned metabolism and protein translation rates. Due to the scarcity of stem cells, it has remained largely unknown how aberrantly elevated Ras signals may impact frequency, lineage potential, and quiescent metabolism in rare HSC. Using single cell proteomics and computational analyses, we characterized the effects of induced oncogenic mutant KRasG12D or overexpression of the Ras activator RasGRP1, compared to normal native hematopoiesis. The two Ras pathway lesions drive shared profound skewing towards and expansion of mature myeloid cells. The resolution of CyTOF unmasked opposing patterns for the HSC- and progenitor- compartments: Overexpression of RasGRP1 induced expansion of both subsets, whereas KRASG12D resulted in depletion. By combining spectral flow with SCENITHÔ, a method to quantitate protein translation as a proxy for metabolic state, we first corroborated that immature cells display low metabolic SCENITHÔ rates. Both RasGRP1 and KRASG12D drive elevated, mean SCENITHÔ signals in immature hematopoietic cells. However, RasGRP1-overexpressing stem cells retain a metabolically quiescent cell-fraction, whereas this fraction is incompatible with KRASG12D. Our temporal proteomics and metabolomics datasets provide mechanistic insights into altered hematopoiesis at single cell resolution and support the idea that the exact identity and duration of signals from Ras lesions has profound impacts on stem cell maintenance and lineage-potential.

DOI: https://doi.org/10.1182/bloodadvances.2024014411
Blood. 2025 Aug 01. pii: blood.2024028079. [Epub ahead of print]

Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.

Abhishek K Singh, Angelo D'Alessandro, Ashley Wellendorf, Daniel Gonzalez-Nieto, Matthew Kofron, Monika Dzieciatkowska, Leo Mejia, Luis Barrio, Marie-Dominique Filippi, Jose A Cancelas.

Hematopoietic stem cells (HSC) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSC and multipotential progenitors (HSC/MPP) are metabolically coupled to bone marrow (BM) mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low AMP-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSC remains elusive. Here, through integrated transcriptomic, proteomic, metabolomic, phenotypic, and functional analyses of HSC and their isolated mitochondria, we identified that Cx43 is present on inner and outer mitochondrial membranes of HSC/MPP, where it primarily regulates mitochondrial metabolism and ATP synthesis by preserving the mitochondrial cristae, activation of mitochondrial AMPK and 2-oxoglutarate dehydrogenase (OGDH)-a rate liming enzyme in TCA cycle and electron transfer chain. During replicative stress, Cx43 deficient HSC/MPP fail to adapt metabolically, accumulate mitochondrial Ca2+, increase mitochondrial AMPK activity, mitochondrial fission, mitophagy, and production of reactive oxygen species, thereby limiting HSC/MPP regeneration potential. Disruption of hyper mitochondrial fragmentation and mitophagy by Drp1 dominant negative mutant (Drp1K38A) or restoration of mitochondrial function through ex vivo heteroplasmy prevent the harmful effects of Cx43 deficiency on mitochondrial metabolism and restore HSC activity in serial transplantation experiments. Re-expression analysis of Cx43 structure function mutants indicate that Cx43 hemichannels are sufficient to reset HSC mitochondrial metabolism, dynamics, Ca2+ levels, and regeneration capacity. This report defines the cell-autonomous mechanism of action behind the role of Cx43 in HSC activity and opens a venue to translational applications in transplantation.

DOI: https://doi.org/10.1182/blood.2024028079
Stem Cells. 2025 Jul 29. pii: sxaf053. [Epub ahead of print]

Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases.

Katherine Hampton, Alyssa Polski-Delve, Charlotte Hellmich, Stuart A Rushworth.

  In steady state, hematopoietic stem cells (HSCs) reside quiescently in their hypoxic niche with minimal mitochondrial activity, maintaining characteristically low levels of reactive oxygen species (ROS) and instead favoring glycolysis to meet their low energy requirements. However, stress, such as acute infection, triggers a state of emergency hematopoiesis during which HSCs expand more rapidly to produce up to ten-fold more downstream differentiated immune cells. To cope with this demand, HSCs increase their energy production by switching from low ATP-yielding glycolysis to high ATP-yielding mitochondrial oxidative phosphorylation. It is this metabolic switch that enables rapid HSC expansion and differentiation into downstream progeny to increase the immune cell pool and effectively clear the infection. This metabolic switch relies on the sufficient availability of healthy mitochondria as well as fuel in the form of free fatty acids to drive the necessary production of cellular components. This concise review aims to focus on how HSCs increase their mitochondrial content and fuel ATP production via fatty acid oxidation and the impact of HSC dysfunction during aging and other metabolic diseases.

Keywords:  Acute myelogenous leukemia (AML); Adult haematopoietic stem cells; Bone marrow; Stem cell expansion; adipose

DOI:  https://doi.org/10.1093/stmcls/sxaf053
Stem Cells. 2025 Jul 29. pii: sxaf054. [Epub ahead of print]

Loss of peroxisome function promotes oxidative stress induced hematopoiesis.

Emma A Schindhelm, Amada Blake, Megan M Constans, Kai Braaten, Aly L Thorn, Willa Durose, Maggie Lorentson, Ashish O Gupta, Paul J Orchard, Nancy Braverman, Gerald V Raymond, Troy C Lund.

  The role of peroxisomes in hematopoiesis remains poorly understood. The PEX1-Gly844Asp knock-in mouse lacks peroxisome formation and is peroxisome deficient. We observed that peroxisome deficient animals had up to 50% greater numbers of peripheral lymphocytes, neutrophils, and platelets which contained 2-fold greater reactive oxygen species (ROS, p = 0.0002). The marrow contained 2-fold greater numbers of cells and CFU (p = 0.0009 and < 0.0001, respectively). We found expansion (up to 3-fold) in the hematopoietic stem and progenitor cell (HSPC) compartment compared to that of WT animals demonstrated by: in vivo enumeration of LSK (p < 0.0001). Importantly through competitive bone marrow transplant experiments (primary and secondary) we show that peroxisome deficient cells outcompete wild type. We further demonstrate that peroxisome deficient HSPC harbor very high levels of intrinsic reactive oxygen species (ROS) which are attenuated after repopulation. Isolation of mesenchymal stem cells (MSC) isolated from peroxisome deficient mice also showed elevated levels of ROS. Finally, we found elevated levels of stem cell factor (SCF) in the plasma of peroxisome deficient mice and peroxisome deficient MSC expressed 2-fold more SCF compared to WT. Chemical induction of ROS also increased SCF expression by MSC. LSK expanded >10-fold greater in the absence on SCF on peroxisome deficient MSC than on WT MSC. In conclusion, the increase in HSPC numbers is, in part, driven by response to ROS in the microenvironment leading to increased SCF. These data add new insight into the role of peroxisomes in the bone marrow niche.

Keywords:  hematopoietic stem cell; mesenchymal stem cell; peroxisome; reactive oxygen species; stem cell factor

DOI:  https://doi.org/10.1093/stmcls/sxaf054
Blood. 2025 Aug 01. pii: blood.2024027822. [Epub ahead of print]

Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.

Cornelius Pauli, Michael Kienhöfer, Maximilian Felix Blank, Oguzhan Begik, Christian Rohde, Sarah Mn Zimmermann, Laura Werner, Daniel Heid, Fu Xu, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Laia Llovera, Ollivier Alexane, Anke Heit-Mondrzyk, Uwe Platzbecker, Claudia D Baldus, Hubert Serve, Martin Bornhäuser, Cathrine B Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, Eva Maria Novoa, Carsten Müller-Tidow, Michaela Frye.

Dysregulated RNA modifications contribute to cancer progression and therapy resistance, yet the underlying mechanism often remains unknown. Here, we perform CRISPR-based synthetic lethality screens to systematically explore the role of RNA modifications in mediating resistance to anti-leukaemic drugs. We identify the TRMT5-mediated formation of N1-methylguanosine (m1G) in the tRNA anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax in acute myeloid leukemia (AML). TRMT5 methylates nearly all mitochondrial and nuclear tRNAs with a guanosine at position 37, but its role in promoting drug tolerance specifically depends on its mitochondrial function. TRMT5 is essential for the dynamic upregulation of mitochondrial mRNA translation and oxidative phosphorylation (OXPHOS), which are critical for sustaining drug tolerance in leukemia cells. This mitochondrial dependency correlates with therapy outcomes in leukemia patients: lower expression of electron transport chain genes is linked to poorer outcomes in a cohort of nearly 100 AML patients undergoing first induction therapy. Finally, we demonstrate that targeted depletion of TRMT5 protein using a conditional degron, in conjunction with cytarabine and venetoclax treatment, synergistically induces cell death in drug-tolerant AML cells. Thus, our study reveals TRMT5 as promising drug target for therapy-resistant leukemia.

DOI: https://doi.org/10.1182/blood.2024027822
Cell Rep. 2025 Jul 30. pii: S2211-1247(25)00858-7. [Epub ahead of print]44(8): 116087

Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML.

Hong Zheng, Peng Zhao, Zhenya Tan, Wen-Mei Yu, Juwita Werner, Elliot Stieglitz, Christopher C Porter, Shanmuganathan Chandrakasan, Daniel S Wechsler, Simon Mendez-Ferrer, Cheng-Kui Qu.

  Juvenile myelomonocytic leukemia (JMML) originates from mutated hematopoietic stem cells. The mechanism by which mutant stem cells are sustained, leading to leukemia development, remains elusive. By comprehensively examining transcriptomic profiles, cell compositions, developmental trajectories, and cell-cell interactions across various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML, we find that Ptpn11E76K/+ mutant stem cells exhibit de novo activation of the myeloid transcriptional program and markedly increased expression of innate immunity-associated antimicrobial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8. Biological experiments confirm that S100a9/S100a8 confer a selective advantage to mutant stem cells through autocrine effects and facilitate immune evasion by recruiting and promoting immune-suppressive myeloid-derived suppressor cells in the microenvironment. Importantly, pharmacological inhibition of S100a9/S100a8 signaling effectively impede leukemia development from Ptpn11E76K/+ mutant stem cells. These findings collectively suggest that JMML-initiating cells exploit innate immune and inflammatory mechanisms to establish clonal dominance.

Keywords:  CP: Cancer; CP: Immunology; JMML; PTPN11; S100a8; S100a9; hematopoietic stem cell; inflammation; innate immunity; leukemia-initiating cell

DOI:  https://doi.org/10.1016/j.celrep.2025.116087
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251363050

Membrane Contact Sites in Proteostasis and ER Stress Response.

Febe Vermue, Aysegul Sapmaz, Ilana Berlin.

  Execution of all cellular functions depends on a healthy proteome, whose maintenance requires multimodal oversight. Roughly a third of human proteins reside in membranes and thus present unique topological challenges with respect to biogenesis and degradation. To meet these challenges, eukaryotes have evolved organellar pathways of protein folding and quality control. Most transmembrane proteins originate in the endoplasmic reticulum (ER), where they are subject to surveillance and, if necessary, removal through either ER-associated proteasomal degradation (cytosolic pathway) or selective autophagy (ER-phagy; organellar pathway). In the latter case, ER cargoes are shuttled to (endo)lysosomes - the same organelles that degrade cell surface molecules via endocytosis. Here, we provide an overview of dynamic coordination between the ER and endolysosomes, with a focus on their engagement in specialized physical interfaces termed membrane contact sites (MCSs). We cover how cross-compartmental integration through MCSs allows biosynthetic and proteolytic organelles to fine-tune each other's membrane composition, organization, and dynamics and facilitates recovery from proteotoxic stress. Along the way, we highlight recent developments and open questions at the crossroads between organelle biology and protein quality control and cast them against the backdrop of factor-specific diseases associated with perturbed membrane homeostasis.

Keywords:  endolysosome; endoplasmic reticulum; membrane contact sites; proteostasis; proteotoxic stress

DOI:  https://doi.org/10.1177/25152564251363050
Cell. 2025 Jul 25. pii: S0092-8674(25)00750-0. [Epub ahead of print]

Human interpretable grammar encodes multicellular systems biology models to democratize virtual cell laboratories.

Jeanette A I Johnson, Daniel R Bergman, Heber L Rocha, David L Zhou, Eric Cramer, Ian C Mclean, Yoseph W Dance, Max Booth, Zachary Nicholas, Tamara Lopez-Vidal, Atul Deshpande, Randy Heiland, Elmar Bucher, Fatemeh Shojaeian, Matthew Dunworth, André Forjaz, Michael Getz, Inês Godet, Furkan Kurtoglu, Melissa Lyman, John Metzcar, Jacob T Mitchell, Andrew Raddatz, Jacobo Solorzano, Aneequa Sundus, Yafei Wang, David G DeNardo, Andrew J Ewald, Daniele M Gilkes, Luciane T Kagohara, Ashley L Kiemen, Elizabeth D Thompson, Denis Wirtz, Laura D Wood, Pei-Hsun Wu, Neeha Zaidi, Lei Zheng, Jacquelyn W Zimmerman, Jude M Phillip, Elizabeth M Jaffee, Joe W Gray, Lisa M Coussens, Young Hwan Chang, Laura M Heiser, Genevieve L Stein-O'Brien, Elana J Fertig, Paul Macklin.

  Cells interact as dynamically evolving ecosystems. While recent single-cell and spatial multi-omics technologies quantify individual cell characteristics, predicting their evolution requires mathematical modeling. We propose a conceptual framework-a cell behavior hypothesis grammar-that uses natural language statements (cell rules) to create mathematical models. This enables systematic integration of biological knowledge and multi-omics data to generate in silico models, enabling virtual "thought experiments" that test and expand our understanding of multicellular systems and generate new testable hypotheses. This paper motivates and describes the grammar, offers a reference implementation, and demonstrates its use in developing both de novo mechanistic models and those informed by multi-omics data. We show its potential through examples in cancer and its broader applicability in simulating brain development. This approach bridges biological, clinical, and systems biology research for mathematical modeling at scale, allowing the community to predict emergent multicellular behavior.

Keywords:  agent-based modeling; cancer biology; cell behavior hypothesis grammar; cell behaviors; cell interactions; immunology; immunotherapy; mathematical biology; mathematical modeling; modeling language; multi-omics; multicellular systems; multicellular systems biology; physics of multicellular biology; simulation; spatial transcriptomics; tissue dynamics

DOI:  https://doi.org/10.1016/j.cell.2025.06.048
Nat Commun. 2025 Jul 29. 16(1): 6617

Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis.

Tze Mun Loo, Xiangyu Zhou, Yoko Tanaka, Sho Sugawara, Shota Yamauchi, Hiroko Kawasaki, Yuta Matsuoka, Yuki Sugiura, Shinya Sakuma, Yoko Yamanishi, Satoshi Yotsumoto, Kosuke Dodo, Yoshitaka Shirasaki, Takashi Kamatani, Akiko Takahashi.

Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis. Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.

DOI: https://doi.org/10.1038/s41467-025-61894-9
Blood Neoplasia. 2025 Aug;2(3): 100107

Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML.

Mengdan Liu, Ming Yan, Amanda G Davis, Samuel A Stoner, Edward D Ball, Dong-Er Zhang.

Acute myeloid leukemia (AML) is a blood cancer complicated by acquired drug resistance, disease relapse, and low overall survival rates. Combination therapies using multiple targeted inhibitors have been effective in treating patients with AML. However, combination treatments are limited by the number of usable targets and our ability to create rational pairings using complimentary molecular mechanisms. Here, we used a human kinase domain-targeted CRISPR screen to identify histone H3-associated protein (HASPIN) kinase as a significant, understudied dependency in AML. HASPIN depletion significantly reduced growth rate, induced a cell cycle arrest, and dysregulated transcription in AML. A proteomics data mining study characterized serine and arginine repeat enriched splicing factors (SR proteins) as a major category of HASPIN kinase substrates and highlighted the role of HASPIN as a splicing regulatory kinase. Accordingly, HASPIN depletion strongly dysregulated splicing in AML cells. HASPIN inhibitor CHR-6494 effectively reduced cell viability across AML subtypes while sparing healthy cells. Furthermore, a novel combination therapy consisting of CHR-6494 and B-cell lymphoma 2 (BCL-2) inhibitor venetoclax synergistically reduced AML cell viability and resensitized venetoclax-resistant AMLs to treatment. Our study presents HASPIN kinase as a novel therapeutic target for AML, underscores an underappreciated role of HASPIN in splicing regulation, and proposes a viable combination treatment for clinical testing.

DOI: https://doi.org/10.1016/j.bneo.2025.100107