bims-mithem 2026-08-02 papers

Issue of 2026–08–02
five papers selected by
Tim van Tienhoven, Erasmus Medical Center

bioRxiv. 2026 Jul 17. pii: 2026.07.16.736849. [Epub ahead of print]

Targeting cellular senescence alleviates bone marrow aging.

Bowen Yan, Jin Han, Yang Yang, Peiyi Zhang, Jason O Brant, Jianhui Chang, Ha-Neui Kim, Maria Almeida, Prabhjot Kaur, Qingchen Yuan, Marco Demaria, Kalyanee Shirlekar, Jennifer Elisseeff, Guangrong Zheng, Ying Liang, Daohong Zhou, Olga A Guryanova.

Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.

DOI: https://doi.org/10.64898/2026.07.16.736849

Signal Transduct Target Ther. 2026 Jul 29. pii: 295. [Epub ahead of print]11(1):

Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.

Agustina Creus, Shrestha Mohapatra, Leonardo Ortega, David Sebastián.

Mitochondria are essential for cellular homeostasis, integrating various signals to control key cellular functions such as metabolism, apoptosis, inflammation, cell proliferation and redox balance. Given their multifaceted functions, it is not surprising that mitochondrial dysfunction has been implicated as a key contributor to the pathogenesis of numerous human diseases. Consequently, preserving mitochondrial integrity and functionality is vital for overall organismal health. Mitochondrial health is safeguarded by a sophisticated and tightly regulated network of quality control systems. These include mitochondrial proteostasis, which ensures proper protein folding and degradation; mitochondrial biogenesis, which governs the synthesis of new mitochondria; mitochondrial dynamics, encompassing fusion and fission processes; and mitophagy, the selective autophagic removal of damaged mitochondria. Additionally, these core systems are intricately connected to other crucial mitochondrial processes, such as the maintenance of mitochondrial DNA integrity, the regulation of cristae architecture, and the control of mitochondrial permeability transition, all of which are indispensable for optimal mitochondrial performance. Preclinical and clinical studies consistently demonstrate a strong link between impairments in these quality control mechanisms and both aging and the development of a wide spectrum of diseases. These include cancer, metabolic disorders, cardiovascular conditions, neurodegenerative diseases and autoimmune pathologies. In this review, we explore the different facets of mitochondrial quality control and discuss their implications in disease progression and aging. Furthermore, we highlight recent advances in interventions and therapies aimed at modulating mitochondrial quality control, providing an overview of their potential to mitigate disease burden and promote healthy aging.

DOI: https://doi.org/10.1038/s41392-026-02813-2

Biomolecules. 2026 Jul 01. pii: 972. [Epub ahead of print]16(7):

Mitochondrial Dysfunction in Circulating Blood Cells and Biological Aging: A Review of Mechanisms and Evidence.

Abdullah M AlShahrani, S Rehan Ahmad.

Chronological age tells us how long a person has lived-but not how well. Two individuals of the same age can differ dramatically in their cellular health, disease risk, and functional capacity. This gap between calendar age and biological age has driven growing interest in biomarkers that reflect true cellular aging rather than years lived. Mitochondria sit at the heart of this problem. Far more than cellular power plants, these organelles govern energy production, oxidative stress, immune signaling, and programmed cell death. As the body ages, mitochondria deteriorate in consistent and measurable ways-and crucially, these changes can be detected in circulating blood cells, offering a minimally invasive window into the body's biological age. This narrative review synthesizes two decades of research (2005-2025) on three blood-based mitochondrial markers: mitochondrial DNA copy number (mtDNA-CN) in peripheral blood mononuclear cells, mitochondrial membrane potential (MMP), and cell-free mitochondrial DNA (cf-mtDNA) in plasma. Across 68 carefully selected studies, we evaluate the strength, consistency, and clinical relevance of each marker, alongside their associations with cardiovascular disease, metabolic dysfunction, cognitive decline, and mortality. The evidence is promising but still maturing. Significant methodological variation across studies limits direct comparisons, and robust prospective outcome data remain limited. We propose a four-phase framework for responsible clinical translation and identify specific research investments needed-from measurement standardization to large cohort studies and intervention trials-before these markers can responsibly inform patient care.

Keywords: aging biomarkers; biological aging; cell-free mitochondrial DNA; clinical translation; inflammaging; mitochondrial dysfunction; mitochondrial membrane potential; mtDNA copy number; oxidative stress; peripheral blood mononuclear cells

DOI: https://doi.org/10.3390/biom16070972

Blood Adv. 2026 Jul 30. pii: bloodadvances.2026019909. [Epub ahead of print]

Chromatin Accessibility Shapes Developmental-Specific Lineage Plasticity in Hematopoiesis.

Sara Palo, Keiki Nagaharu, Mikael N E Sommarin, Rasmus Olofzon, Virginia Turati, Shamit Soneji, Göran Karlsson, Charlotta Böiers.

Cell differentiation is governed by dynamic changes in chromatin accessibility, and its dysregulation underlies multiple disease states. Prior to birth, development of the hematopoietic system constitutes a period of broad differentiation potential, with certain immune cells arising exclusively during ontogeny. While age is known to affect lineage bias, the underlying molecular differences driving lineage preference in fetal and adult human hematopoietic stem and progenitor cells (HSPCs) remain unclear. Through single-cell cultures of hematopoietic stem cells (HSCs), we observed that fetal cells frequently generate mixed-lineage colonies, whereas adult HSCs are biased towards myeloid output. To investigate how these lineage preferences were encoded at the chromatin level, we performed single-cell ATAC-sequencing on first-trimester HSPCs. While adult HSCs showed enrichment of lineage-specific transcription factor motifs, fetal cells lacked such enrichment, consistent with their broader differentiation potential. We additionally uncovered a developmental-specific plasticity in fetal lymphoid progenitors, manifested as a hybrid lympho-myeloid chromatin program not present in adult progenitors. Additionally, the motif and putative regulatory elements for PAX5, a master regulator of B cell development, showed markedly reduced accessibility in fetal cells, supporting a more plastic and less restricted lymphoid state. This enhanced embryonic lineage plasticity may underlie the prenatal susceptibility to mutational drivers of acute lymphoblastic leukemia.

DOI: https://doi.org/10.1182/bloodadvances.2026019909

J Genet Genomics. 2026 Jul 25. pii: S1673-8527(26)00242-0. [Epub ahead of print]

Prdm15 deficiency perturbs hematopoietic stem and progenitor cell homeostasis.

Qiwen Dong, Weiwei Xiao, Junsong Huang, Zheng Sun, Min Liang, Mengjiao Wang, Qingqing Wang, Xinlan Zong, Anzi Li, Yan Wang, Zhongsheng Sun.

The maintenance of homeostasis in hematopoietic stem and progenitor cells (HSPCs) is essential for the proper development of the entire hematopoietic system. However, the mechanisms underlying this regulatory equilibrium remain elusive. Here, we report that Prdm15 deficiency in HSPCs induces the accumulation of immature hematopoietic stem cells in mice. A series of transplantation assays shows that these cells display impaired reconstitution capacity and competitive fitness, which are associated with abnormal differentiation trajectories and transcriptional alterations identified by single-cell RNA sequencing. Mechanistically, integrated multi-omics analyses including ATAC-seq and CUT&Tag sequencing of HSPCs indicate that Prdm15 deficiency induces significant transcriptional and epigenetic alterations, particularly affecting the methyltransferase KMT2C and altering H3K4me1 and H3K27ac modifications at the promoters of hematopoietic developmental genes. Collectively, our findings establish PRDM15 as a critical epigenetic regulator of HSPCs, offering valuable insights into the molecular mechanisms underlying hematopoietic homeostasis.

Keywords: Cell differentiation; Epigenetics; Hematopoietic homeostasis; Hematopoietic stem and progenitor cells; PRDM15

DOI: https://doi.org/10.1016/j.jgg.2026.07.009