bims-mithem 2026-02-15 papers

bims-mithem

Biomed News

on Mitochondria in Hematopoiesis

Issue of 2026–02–15
nine papers selected by
Tim van Tienhoven, Erasmus Medical Center

Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.
Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.
Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
Clonal Hematopoiesis and Its Cardiovascular Implications: A Scientific Statement From the American Heart Association.
Leptin Receptor + cells create a perisinusoidal niche for thrombopoiesis in the bone marrow by synthesizing CXCL14.
Mechanisms and disease relevance of mitochondrial translation in humans.
Systems-level modelling of DNA damage, senescence, and stem cell dynamics in ageing.
Mitochondria-targeted delivery strategies for age-related diseases.
Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.

Blood Cancer Discov. 2026 Feb 10. OF1-OF13

Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.

Yutang Li, Xinting Hu, Xiangxiang Zhou.

Mitochondria regulate critical cellular processes beyond energy production, including organelle quality control, programmed cell death, and intercellular and interorganellar communication. In hematologic malignancies, mitochondria undergo adaptations through mechanisms including genetic mutations, metabolic reprogramming, mitochondrial transfer, fusion, and mitophagy. These alterations create heterogeneity, contribute to therapeutic resistance, and can also reshape the tumor microenvironment to promote progression. Collectively, these findings suggest that mitochondria represent a promising frontier in next-generation therapeutics, with emerging strategies such as mitochondrial-targeted small molecules and mitochondrial transplantation holding significant therapeutic potential.
SIGNIFICANCE: In this review, we summarize the functions of mitochondria beyond energy production and highlight the heterogeneity of mitochondrial functional adaptations in hematologic malignancies, as well as the vital role of mitochondrial alterations in reshaping the tumor microenvironment. Understanding these changes is critical to deciphering the pathophysiology of hematologic malignancies.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0338
Arch Toxicol. 2026 Feb 07.

Targeting the powerhouse: the mitochondrial perspective on gentamicin-induced kidney injury.

Busra Korkut Celikates, Sinem Ilgin, Melis Umay Yilmaz, Ozlem Atli Eklioglu.

  Gentamicin (GEN), an aminoglycoside antibiotic, induces nephrotoxicity primarily via mitochondrial dysfunction. This review summarizes mechanisms including reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impairment of oxidative phosphorylation, and mitochondrial permeability transition pore (mPTP) activation. These mitochondrial alterations lead to adenosine triphosphate (ATP) depletion, apoptosis, and renal injury. In addition to apoptotic pathways, necrotic cell death can also be triggered, further aggravating kidney damage. Furthermore, GEN has been reported to directly interfere with mitochondrial ribosomes and gene expression, highlighting mitochondria as both targets and amplifiers of cellular toxicity. Therapeutic approaches targeting mitochondrial integrity, including antioxidants and mitochondrial transplantation, demonstrate potential nephroprotection. Additional strategies such as mPTP, stimulation of mitochondrial biogenesis, and pharmacological modulators of mitochondrial respiration have also shown promise in experimental studies. Understanding mitochondrial mechanisms underlying gentamicin-induced renal injury is crucial for developing targeted therapeutic strategies. A more comprehensive knowledge of mitochondrial regulation, organelle crosstalk, and early biomarkers of dysfunction will facilitate translation into clinical practice. Overall, preserving mitochondrial function represents a promising avenue for reducing nephrotoxicity while maintaining the antibacterial efficacy of GEN.

Keywords:  Gentamicin; Mitochondrial dysfunction; Mitochondrial permeability transition pore; Nephrotoxicity; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00204-026-04310-5
Nat Commun. 2026 Feb 12. 17(1): 1645

Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.

Veronica Bergo, Pavlos Bousounis, Giang To Vu, Mélodie Douté, Aikaterini Polyzou, Maria-Eleni Lalioti, Bogdan B Grigorash, Lyudmila Tsurkan, Nicholas Morchel, Ward Deboutte, Frédéric Brau, Thomas Manke, Sagar, Hind Medyouf, Dmitry V Bulavin, Nina Cabezas-Wallscheid, Marta Derecka, Eirini Trompouki.

"Inflammaging", the chronic increase in inflammatory signaling with age, remains poorly understood in hematopoietic aging. Here, we identify the innate immune RNA sensor melanoma differentiation-associated protein 5 (MDA5) as an important factor of hematopoietic stem cell (HSC) aging. Aged Mda5-/- mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged Mda5-/- HSCs retain greater quiescence and superior repopulation capacity in noncompetitive transplants compared to wild-type counterparts. Multiomic analyses- including chromatin accessibility, transcriptomics, and metabolomics-reveal decreased inflammatory signaling, a youthful metabolic profile, and improved proteostasis in Mda5-/- HSCs, through regulation of HSF1 and phospho-EIF2A, key proteostasis regulators. Activation of HSF1 in aged wild-type HSCs partially restores youthful features, supporting a causal role for proteostasis maintenance. Collectively, our findings demonstrate that attenuating MDA5-dependent inflammation preserves HSC function during aging by maintaining metabolic fitness and proteostasis and provide insight into potential therapeutic strategies for mitigating hematopoietic aging.

DOI: https://doi.org/10.1038/s41467-026-69424-x
Circulation. 2026 Feb 10.

Clonal Hematopoiesis and Its Cardiovascular Implications: A Scientific Statement From the American Heart Association.

American Heart Association Molecular Determinants of Cardiovascular Health Committee of the Council on Genomic and Precision Medicine and Council on Epidemiology and Prevention; and the Cardio-Oncology Committee of the Council on Clinical Cardiology and Council on Epidemiology and Prevention

  Clonal hematopoiesis (CH), the benign clonal expansion of hematopoietic stem cells, is often caused by somatic sequence variations in genes associated with hematologic malignancies. Over the past decade, CH has emerged as a risk factor for a wide range of cardiovascular diseases (CVDs), including atherosclerosis, heart failure, atrial fibrillation, and thrombosis. The cardiovascular risk associated with CH is heterogeneous; it varies on the basis of specific genes and variants, clone size, and various extrinsic features. Mechanistic studies suggest that CH contributes to CVDs through both gene-specific pathways and broader inflammatory processes. These include aberrant cytokine production, inflammasome activation, and other proinflammatory mechanisms, which can accelerate atherosclerosis, promote thrombogenesis, and impair vascular or myocardial function. These findings underscore the importance of addressing CH as a potential contributor to CVDs. CH is predominantly considered an age-related phenomenon, but lifelong influences on the fitness of genetic variants, including germline predispositions, obesity, chronic inflammation, and exposure to environmental toxins (eg, tobacco, certain cancer treatments), influence CH. A greater understanding of CH risk factors is therefore important for both individual and population-level risk assessments. Incorporating CH-associated risk into existing CVD risk prediction models may inform new personalized preventive or therapeutic approaches. No CH-specific therapies have proven efficacy in CVD treatment or prevention, but multiple molecular-based therapeutic hypotheses are beginning to be tested.

Keywords:  AHA Scientific Statements; aging; cardiovascular diseases; clonal hematopoiesis; heart failure; hematopoietic stem cells; mutation

DOI:  https://doi.org/10.1161/CIR.0000000000001404
bioRxiv. 2026 Jan 28. pii: 2026.01.27.702029. [Epub ahead of print]

Leptin Receptor + cells create a perisinusoidal niche for thrombopoiesis in the bone marrow by synthesizing CXCL14.

Yuanyuan Xue, Salma Merchant, Amanda Reyes, Maowu Luo, Ruixuan Zhang, Trevor Tippetts, Gerik Grabowski, Tai Ngo, Yanan Zhang, Zhiguo Shang, Nisi Jiang, Elise Jeffery, Yafeng Li, Tao Wei, Wen Gu, Liming Du, Ralph J DeBerardinis, Kevin M Dean, Thomas P Mathews, Daniel Lucas, Zhiyu Zhao, Sean J Morrison.

Leptin Receptor-expressing (LepR + ) stromal cells in the bone marrow are a critical source of growth factors for the maintenance of hematopoietic stem cells (HSCs) and most restricted hematopoietic progenitors. An important unresolved question is whether they also regulate terminal differentiation in some hematopoietic cells. We found that LepR + cells promote thrombopoiesis by synthesizing the chemokine CXCL14, which is expressed in the bone marrow by a subset of LepR + cells. Cxcl14 -expressing LepR + cells extend fine processes that wrap around perisinusoidal megakaryocytes. Deletion of Cxcl14 from LepR + cells did not significantly alter HSC function or most aspects of bone marrow hematopoiesis, including megakaryocyte generation; however, it significantly reduced the numbers of proplatelet-forming megakaryocytes in the bone marrow and platelets in the blood. CXCL14 promoted platelet formation by remodeling lipid metabolism in megakaryocytes, increasing fatty acid transporter expression and enabling megakaryocytes to use more polyunsaturated fatty acids from the circulation. A high fat diet rescued the formation of proplatelet-forming megakaryocyte and platelets in Lepr-cre; Cxcl14 fl/fl mice. CXCL14 protein was sufficient to promote platelet formation by megakaryocytes in vitro and in vivo. LepR + cells thus create a perisinusoidal niche for thrombopoiesis by producing CXCL14, which regulates lipid metabolism and terminal differentiation in megakaryocytes.
Key points: Leptin Receptor + stromal cells regulate terminal differentiation in megakaryocytes in addition to maintaining stem and progenitor cells CXCL14 from Leptin Receptor + cells promotes the formation of platelets by remodeling lipid metabolism in megakaryocytes in the bone marrow.

DOI: https://doi.org/10.64898/2026.01.27.702029
Nat Rev Mol Cell Biol. 2026 Feb 13.

Mechanisms and disease relevance of mitochondrial translation in humans.

Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.

Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.

DOI: https://doi.org/10.1038/s41580-026-00948-2
Exp Gerontol. 2026 Feb 11. pii: S0531-5565(26)00041-0. [Epub ahead of print] 113063

Systems-level modelling of DNA damage, senescence, and stem cell dynamics in ageing.

Anchen Che, Amy E Morgan, Mark T Mc Auley.

  Ageing entails a variety of cellular and physiological changes that increase susceptibility to disease and death. A significant contributor to ageing is cellular senescence, a state of irreversible cell cycle arrest triggered by stressors such as DNA damage, telomere shortening, and the senescence-associated secretory phenotype. It is challenging to understand the nonlinear interactions between these complex mechanisms using conventional laboratory approaches. Mathematical modelling is capable of representing this complexity. In this study we introduce a mathematical model that captures the dynamics of cellular ageing within a population of cells. The model integrates key processes including DNA damage repair, senescence, quiescence, apoptosis, and cell division. The model was used to simulate the effects of ageing and to evaluate the efficacy of several interventions, including senolytics, telomere length preservation, and stem cell therapy. Deterministic and stochastic simulations reproduce core ageing features: progressive accumulation of senescent cells, a generation distribution centred near experimentally observed Hayflick limits, and an exponential-like age distribution of non-senescent cells. This model captures the long-lasting effects of interventions such as telomere lengthening and stem-cell therapy. It offers a quantitative, extendable platform that supports hypothesis testing and helps identify which ageing interventions warrant experimental validation. Overall, it provides a predictive framework for interpreting cellular ageing and for guiding future experimental work.

Keywords:  Cellular senescence; Longevity; Mathematical modeling; Senolytics; Stem cell therapy; Telomere lengthening

DOI:  https://doi.org/10.1016/j.exger.2026.113063
Int J Pharm X. 2026 Jun;11 100494

Mitochondria-targeted delivery strategies for age-related diseases.

Zefan Liu, Pei Yang, Guilin Cheng, Xin Kang, Lian Li, Yucheng Xiang.

  Aging is a complex progress accompanied with the progressive deterioration of physiological functions and a marked elevation in mortality risk. Among prominent aging theories, the free radical theory and the mitochondrial dysfunction hypothesis have gained significant attention. Thus, targeted delivery of therapeutic drug to mitochondria might be able to alleviate the mitochondrial dysfunction induced by reactive oxygen species. This review summarizes the possible molecular mechanisms between mitochondrial dysfunction and aging progression. Especially, the recent breakthroughs of mitochondrial-targeted delivery platforms for therapeutics against aging progress. Innovative strategies, including small molecular modification, mitochondrial targeting functional peptide guided delivery and some other strategies are discussed. Their translational potential in anti-aging interventions is evaluated. We anticipate that mitochondria-targeted anti-aging therapeutics will soon enter clinical translation, offering potential solutions to address current age-related challenges.

Keywords:  Age-Related Diseases; Mitochondrial Dysfunction; Mitochondrial-Targeted Delivery

DOI:  https://doi.org/10.1016/j.ijpx.2026.100494
iScience. 2026 Feb 20. 29(2): 114738

Heritable ER stress impairs mitochondrial metabolism and maintenance of hematopoietic stem cells after low-dose irradiation.

Stephanie G Moreno, Federica Ferri, Daniel Lewandowski, Vilma Barroca, Saiyiramii Devanand, Nathalie Dechamps, Paul-Henri Romeo, Nathalie Gault.

  How hematopoietic stem cells (HSCs) respond to low doses of radiation currently used in medicine is largely unknown. Here, we show that HSC exposed to a single 20 mGy dose of irradiation (20 mGy-HSC) exhibit, when proliferating, oxidative stress and altered metabolism associated with increased mitochondrial reactive oxygen species and mitochondrial Ca2+ overload. These mitochondrial defects arise from immediate and sustained endoplasmic reticulum (ER) stress, induced by proliferative 20 mGy-HSC through the activation of the eIF2α-ATF4 branch of the unfolded protein response (UPR). The ER stress is heritable and leads, in long-term quiescent 20 mGy-HSC, to the activation of the IRE1α-Xbp1 branch of UPR, which fails to restore ER homeostasis, resulting in a decreased long-term HSC pool. Finally, we show that this heritable ER stress leads to global DNA hypomethylation, partially reversed by the early inhibition of ER stress. Our studies illuminate how adaptive ER stress responses can lead to mitochondrial defects and HSC dysfunctions.

Keywords:  Cell biology

DOI:  https://doi.org/10.1016/j.isci.2026.114738