bims-mithem 2025-08-31 papers

bims-mithem

Biomed News

on Mitochondria in Hematopoiesis

Issue of 2025–08–31
ten papers selected by
Tim van Tienhoven, Erasmus Medical Center

Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.
Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.
Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.
Bone marrow adipocytes: key players in vascular niches, aging, and disease.
Cellular Models of Aging and Senescence.
A Novel Therapeutic Strategy for Bone Marrow Failure: Niche Rejuvenation Using Costal Cartilage-Derived Stem Cells.
Alteration of long- and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis.
The Role of Mitochondrial DNA in Modulating Chemoresistance in Esophageal Cancer: Mechanistic Insights and Therapeutic Potential.
The Mitochondrial Permeability Transition Pore in Platelets: Mechanisms, Physiological Roles, and Therapeutic Perspectives.
Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons.

Aging (Albany NY). 2025 Aug 25. 17

Mitochondrial proteins as biomarkers of cellular senescence and age-associated diseases.

Anna Panfilova, Tatiana Zubareva, Ekaterina Mironova, Gianluigi Mazzoccoli, Maria Greta Pia Marasco, Sofya Balazovskaia, Peter Yablonsky, Igor Kvetnoy.

  Research in the field of mitochondrial biomarkers plays an important role in understanding the processes of cellular aging. Mitochondria are not only the energy centers of the cell, but also key regulators of signaling within the cell. They significantly affect the life and function of the cell. The aging process of cells is associated with various factors, including DNA damage, disruption of the cell cycle, changes in mitochondria, and problems with signal transmission. Mitochondrial dysfunction is a major contributor to cellular and organismal aging. As we age, there is an accumulation of dysfunctional mitochondria, leading to decreased efficiency of oxidative phosphorylation and increased production of reactive oxygen species. This review focuses on the main mitochondrial markers involved in the mechanisms of cell aging: DRP1, Prohibitin, Parkin, PINK1, MFF, VDAC, TOM. These signaling molecules are involved in mitochondrial fission and the mechanisms of mitochondria-dependent apoptosis, in the regulation of mitochondrial respiratory activity, ensuring the stability of the organization and copying of mitochondrial DNA, protecting cells from oxidative stress, in the process of autophagy of damaged mitochondria, in protective mechanisms during stress-induced mitochondrial dysfunction. Analysis of mitochondrial markers can provide valuable information about the state of cells and their functional significance at various stages of aging, which could promote our understanding of cellular aging mechanisms and developing corrective methods. These insights highlight mitochondrial proteins as potential therapeutic targets to combat age-related diseases.

Keywords:  age-associated diseases; biomarkers; cellular senescence; mitochondria; mitochondrial proteins

DOI:  https://doi.org/10.18632/aging.206305
Biochem Soc Trans. 2025 Aug 26. pii: BST20253044. [Epub ahead of print]

Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.

Megan J Baker, Kai Qi Yek, Diana Stojanovski.

  Intrinsic protein quality control (QC) mechanisms are essential in maintaining mitochondrial health and function. These sophisticated molecular machineries govern protein trafficking and import, processing, folding, maturation and degradation, ensuring the organelle's health. Disruption in mitochondrial protein QC can lead to severe, multisystem disorders with variable age of onset and progression. In this review, we provide a snapshot of the intrinsic molecular protein QC machineries in mitochondria detailing their function, localisation and substrate specificity. We also highlight how dysfunction of these molecular machines contributes to mitochondrial disease. Ultimately, elucidating the consequences of proteostatic failure offers critical insights into the pathogenesis of complex mitochondrial disorders.

Keywords:  AAA+; chaperone; disaggregase; extractase; mitochondria; mitochondrial disease; protease; protein quality control

DOI:  https://doi.org/10.1042/BST20253044
Inflammopharmacology. 2025 Aug 27.

Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.

Rufaida Wasim.

  The pathophysiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, is greatly impacted by mitochondrial dysfunction. Recent research suggests that a number of interconnected processes, such as elevated oxidative stress, disturbed energy metabolism, compromised calcium homeostasis, and malformed mitochondrial dynamics, all lead to neuronal injury. The mitochondria in AD brains have structural defects and the function of important oxidative phosphorylation-related enzymes is lowered, which results in less ATP being produced. Further exacerbated by mitochondrial dysfunction is the build-up of amyloid-beta (Aβ) peptides and hyperphosphorylated tau proteins, which interact directly with mitochondrial membranes and proteins to cause mitochondrial fragmentation and hinder mitochondrial transport along neuronal axons. These occurrences cause an increase in reactive oxygen species (ROS) generation, which exacerbates oxidative damage and feeds a vicious cycle. In AD, mutations in mitochondrial DNA (mtDNA) and changes in mitochondrial biogenesis have also been documented, indicating a key involvement in the development of the illness. Preclinical models show promise for therapeutic approaches that attempt to maintain mitochondrial function, including antioxidants, drugs that target the mitochondria. It is crucial to comprehend the intricate relationship between mitochondrial dysfunction and other pathological aspects of AD to find new treatment targets and enhance patient outcomes. In addition to underlining its role in the development of AD, this review examines the complex interaction between mitochondrial dysfunction and AD pathogenesis, taking into account its potential as a biomarker and a target for intervention.

Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Oxidative stress; Pathology

DOI:  https://doi.org/10.1007/s10787-025-01916-6
Front Cell Dev Biol. 2025 ;13 1633801

Bone marrow adipocytes: key players in vascular niches, aging, and disease.

Yonggang Fan, Mai Elkhalek, Yuheng Zhang, Lu Liu, Qi Tian, Nareekarn Chueakula, Saravana K Ramasamy, Rinkoo Dalan, Shukry J Habib, Anjali P Kusumbe.

  Bone marrow adipocytes (BMAs) are emerging as metabolically active endocrine organs within the bone marrow microenvironment, engaging in extensive crosstalk with vascular niches, osteogenic cells, and hematopoietic compartments. In aging and metabolic disorders, mesenchymal and adipocyte progenitors undergo significant quantitative and qualitative transformations that shift from osteogenesis toward adipogenesis. This enhanced adipogenic profile alters the secretion of key adipokines and cytokines, thereby impairing endothelial function, destabilizing the vascular niche, and reducing hematopoietic stem cell support-culminating in bone fragility and disrupted blood cell production. Central to these alterations are pivotal signaling pathways, which orchestrate the interplay between BMAs and their surrounding cells. Furthermore, factors like oxidative stress, chronic inflammation, and endocrine dysregulation modulate BMA behavior and exacerbate their impact on marrow homeostasis. In this comprehensive review, we integrate recent advances that elucidate the molecular and cellular mechanisms underlying BMA function and their complex interactions with vascular niches. We also discuss therapeutic strategies designed to modulate BMA-mediated pathways and their downstream effects on aging and a range of diseases.

Keywords:  aging; bone; bone marrow adipocytes; endothelial cell; vascular niches

DOI:  https://doi.org/10.3389/fcell.2025.1633801
Cells. 2025 Aug 18. pii: 1278. [Epub ahead of print]14(16):

Cellular Models of Aging and Senescence.

Byunggik Kim, Dong I Lee, Nathan Basisty, Dao-Fu Dai.

  Aging, a state of progressive decline in physiological function, is an important risk factor for chronic diseases, ranging from cancer and musculoskeletal frailty to cardiovascular and neurodegenerative diseases. Understanding its cellular basis is critical for developing interventions to extend human health span. This review highlights the crucial role of in vitro models, discussing foundational discoveries like the Hayflick limit and the senescence-associated secretory phenotype (SASP), the utility of immortalized cell lines, and transformative human induced pluripotent stem cells (iPSCs) for aging and disease modeling and rejuvenation studies. We also examine methods to induce senescence and discuss the distinction between chronological time and biological clock, with examples of applying cells from progeroid syndromes and mitochondrial diseases to recapitulate some signaling mechanisms in aging. Although no in vitro model can perfectly recapitulate organismal aging, well-chosen models are invaluable for addressing specific mechanistic questions. We focus on experimental strategies to manipulate cellular aging: from "steering" cells toward resilience to "reversing" age-related phenotypes via senolytics, partial epigenetic reprogramming, and targeted modulation of proteostasis and mitochondrial health. This review ultimately underscores the value of in vitro systems for discovery and therapeutic testing while acknowledging the challenge of translating insights from cell studies into effective, organism-wide strategies to promote healthy aging.

Keywords:  cardiovascular aging; cellular aging; epigenetic reprogramming; in vitro models; induced pluripotent stem cells (iPSCs); mitochondrial dysfunction; neurodegeneration; progeroid syndromes; senescence; senolytics

DOI:  https://doi.org/10.3390/cells14161278
Adv Sci (Weinh). 2025 Aug 27. e07794

A Novel Therapeutic Strategy for Bone Marrow Failure: Niche Rejuvenation Using Costal Cartilage-Derived Stem Cells.

Rui Dong, Zhiguo Ling, Pengyuan Fan, Debao Li, Jinsong Wang, Wenjiong Shi, Rui Zuo, Runfeng Chen, Xuemin Sun, Lang Xiao, Yushi Ran, Shucheng Huang, Yi Tian, Chao Zhang, Yuzhang Wu, Bing Ni, Yi Zhang.

  The bone marrow (BM) niche plays a critical role in maintaining hematopoietic stem cell function but is highly vulnerable to damage from chemotherapy and radiation. However, current therapeutic strategies for BM niche failure remain significantly limited. The previous study demonstrate that costal cartilage-derived stem cells (CDSCs) exhibit substantial self-renewal and bone-forming capacity; however, whether and how CDSCs contribute to BM microenvironment maintenance remains unknown. In this study, the co-transplantation of CDSCs with multipotent progenitors (MPPs) successfully rescued lethally irradiated mice. By contrast, transplantation of mesenchymal stem cells with MPPs or MPPs alone fails to rescue the mice, suggesting a potential role of CDSCs in hematopoietic reconstitution. RNA-seq and experimental data suggest that CDSCs are involved in rejuvenating the BM niche. Mechanistically, CDSCs not only differentiate into niche components, including bone marrow stromal cells, endothelial cells, and osteoblasts, but also secrete pro-hematopoietic cytokines, thereby rejuvenating the irradiated microenvironment. Additionally, CDSCs protect residual hematopoietic stem and progenitor cells from radiation-induced apoptosis and DNA damage while enhancing niche repair. Finally, through synergy with cyclosporine A, CDSCs markedly enhance hematopoietic recovery in mice with aplastic anemia. Collectively, these findings establish CDSCs as a versatile platform for treating BM failure via microenvironmental restoration.

Keywords:  aplastic anemia; bone marrow niche; bone marrow stromal cells; costal cartilage‐derived stem cells; hematopoietic stem cells

DOI:  https://doi.org/10.1002/advs.202507794
Elife. 2025 Aug 27. pii: RP95880. [Epub ahead of print]13

Alteration of long- and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis.

Katsuyuki Nishi, Taro Sakamaki, Akiomi Nagasaka, Kevin Shuolong Kao, Kay Sadaoka, Masahide Asano, Nobuyuki Yamamoto, Akifumi Takaori-Kondo, Masanori Miyanishi.

  Myeloid-biased hematopoiesis is a well-known age-related alteration. Several possibilities, including myeloid-biased hematopoietic stem cell (HSC) clones, may explain this. However, the precise mechanisms remain controversial. Utilizing the Hoxb5 reporter system to prospectively isolate long-term HSCs (LT-HSCs) and short-term HSCs (ST-HSCs), we found that young and aged LT-HSCs co-transplanted into the same recipients demonstrated nearly equivalent myeloid lineage output, contrary to the theory of myeloid-biased HSC clones. Transcriptomics indicated no significant myeloid gene enrichment in aged LT-HSCs compared to their young counterparts. Instead, transplanting reconstituted young HSCs with the ratio of LT/ST-HSCs seen in aged mice can significantly skew the lineage output to myeloid cells. In addition, while the niche environment in the bone marrow minimally affects myeloid-biased hematopoiesis, aged thymi and spleens substantially hinder lymphoid hematopoiesis, resulting in further myeloid domination. Thus, we demonstrate that myeloid-biased hematopoiesis in aged mice originates due to alteration of the ratio between LT-HSCs and ST-HSCs rather than in heterogeneous HSC clones with various cell fates.

Keywords:  aging; developmental biology; long-term hematopoietic stem cell; mouse; myeloid bias; regenerative medicine; self-renewal; short-term hematopoietic stem cell; stem cells

DOI:  https://doi.org/10.7554/eLife.95880
Biomolecules. 2025 Aug 05. pii: 1128. [Epub ahead of print]15(8):

The Role of Mitochondrial DNA in Modulating Chemoresistance in Esophageal Cancer: Mechanistic Insights and Therapeutic Potential.

Koji Tanaka, Yasunori Masuike, Yuto Kubo, Takashi Harino, Yukinori Kurokawa, Hidetoshi Eguchi, Yuichiro Doki.

  Chemotherapy remains a cornerstone in the treatment of esophageal cancer (EC), yet chemoresistance remains a critical challenge, leading to poor outcomes and limited therapeutic success. Mitochondrial DNA (mtDNA) has emerged as a pivotal player in mediating these responses, influencing cellular metabolism, oxidative stress regulation, and apoptotic pathways. This review provides a comprehensive overview of the mechanisms by which mtDNA alterations, including mutations and copy number variations, drive chemoresistance in EC. Specific focus is given to the role of mtDNA in metabolic reprogramming, including its contribution to the Warburg effect and lipid metabolism, as well as its impact on epithelial-mesenchymal transition (EMT) and mitochondrial bioenergetics. Recent advances in targeting mitochondrial pathways through novel therapeutic agents, such as metformin and mitoquinone, and innovative approaches like CRISPR/Cas9 gene editing, are also discussed. These interventions highlight the potential for overcoming chemoresistance and improving patient outcomes. By integrating mitochondrial diagnostics with personalized treatment strategies, we propose a roadmap for future research that bridges basic mitochondrial biology with translational applications in oncology. The insights offered in this review emphasize the critical need for continued exploration of mtDNA-targeted therapies to address the unmet needs in EC management and other diseases associated with mitochondria.

Keywords:  chemotherapy resistance; esophageal cancer; mitochondrial DNA; mitochondrial-targeted therapy; mtDNA mutations; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biom15081128
Antioxidants (Basel). 2025 Jul 29. pii: 923. [Epub ahead of print]14(8):

The Mitochondrial Permeability Transition Pore in Platelets: Mechanisms, Physiological Roles, and Therapeutic Perspectives.

Chiara Lonobile, Alessia Di Nubila, Rosa Simone, Matilda Hushi, Silvia Stella Barbieri.

  Platelets have long been known to be critically involved in hemostasis and thrombosis. However, platelets are also recognized as metabolically active cells that require well-regulated mitochondrial function to support their multiple functions in hemostasis, thrombosis, and inflammation. Mitochondrial activity has also recently been shown to play a crucial role in determining platelet activation, survival, and pro-inflammatory potential. A key nexus in these processes is the mitochondrial permeability transition pore (mPTP), a high-conductance channel in the inner mitochondrial membrane. Sustained mPTP opening triggers mitochondrial depolarization, the cessation of ATP synthesis, osmotic swelling, and, finally, platelet dysfunction or clearance. However, its transient opening might play physiological signaling roles. This review summarizes the current understanding of the molecular components and regulatory factors governing the platelet mPTP, explores its physiological and pathological relevance, and evaluates its potential as a therapeutic target in cardiovascular disease, inflammation, cancer, and potentially neurodegenerative diseases. We also highlight the ongoing challenges and crucial future directions in deciphering the complexities of platelet mitochondrial dynamics and mPTP functions.

Keywords:  mitochondrial permeability transition pore; platelets; therapeutic targets

DOI:  https://doi.org/10.3390/antiox14080923
Antioxidants (Basel). 2025 Aug 12. pii: 987. [Epub ahead of print]14(8):

Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons.

Bojan Stojanovic, Ivan Jovanovic, Milica Dimitrijevic Stojanovic, Bojana S Stojanovic, Vojin Kovacevic, Ivan Radosavljevic, Danijela Jovanovic, Marina Miletic Kovacevic, Nenad Zornic, Ana Azanjac Arsic, Stevan Eric, Nikola Mirkovic, Jelena Nesic, Stefan Jakovljevic, Snezana Lazarevic, Ivana Milivojcevic Bevc, Bojan Milosevic.

  Cellular senescence, a state of permanent cell cycle arrest, represents a double-edged sword in biology-providing tumor-suppressive functions while contributing to tissue degeneration, chronic inflammation, and age-related diseases when senescent cells persist. A key driver of senescence is oxidative stress, primarily mediated by excessive reactive oxygen species that damage mitochondrial DNA, modulate redox-sensitive signaling pathways, and trigger the senescence-associated secretory phenotype. Emerging evidence highlights the pathogenic role of SASP in promoting local inflammation, immune evasion, and senescence propagation. This review explores the intricate interplay between redox imbalance and cellular senescence, emphasizing mitochondrial dysfunction, SASP dynamics, and their implications in aging and cancer. We discuss current senotherapeutic strategies-including senolytics, senomorphics, antioxidants, gene therapy, and immunotherapy-that aim to eliminate or modulate senescent cells to restore tissue homeostasis. Understanding the heterogeneity and context-specific behavior of senescent cells remains crucial for optimizing these therapies. Future research should focus on addressing key knowledge gaps, including the standardization of senescence biomarkers such as circulating miRNAs, refinement of predictive preclinical models, and development of composite clinical endpoints. These efforts are essential to translate mechanistic insights into effective senotherapeutic interventions and enable the safe integration of senescence-targeting strategies into routine clinical practice.

Keywords:  DNA damage response; Nrf2 pathway; SASP; aging; cancer; cellular senescence; mitochondrial dysfunction; oxidativestress; redox signaling; senotherapy

DOI:  https://doi.org/10.3390/antiox14080987