bims-mithem 2026-03-22 papers

Issue of 2026–03–22
four papers selected by
Tim van Tienhoven, Erasmus Medical Center

Aging Cell. 2026 Apr;25(4): e70453

Age-Like Methylation Changes of HSCs in GADD45B Knockout Mice Define Methylation Sites Associated With Loss of Function.

Wakako Kuribayashi, Mayuri Tanaka-Yano, Bongsoo Park, Hagai Yanai, Ferda Tekin-Turhan, Isabel Beerman.

Hematopoietic stem cells (HSCs) self-renew and differentiate into all blood cells maintaining the hematopoietic system. Age-related HSC dysfunction impacts all of hematopoiesis, with DNA methylation alterations in aged HSCs contributing to altered function. Growth Arrest and DNA Damage-inducible proteins (Gadd45a, Gadd45b, and Gadd45g) are expressed in HSC activation, and Gadd45b has been reported to induce DNA demethylation. Thus, we explored the relationship between Gadd45b, DNA methylation and age-related HSC changes. WGBS on HSCs from GADD45B knockout mice demonstrated young knockout HSCs have increased DNA methylation, with both unique and overlapping methylation changes compared to aged wild-type HSCs without reflecting aging transcriptional changes. Peripheral blood and bone marrow analysis, competitive transplants, and single-cell culture analyses showed no significant loss of functional potential in the aberrantly methylated GADD45B knockout HSCs. We concluded these altered methylation sites don't alter HSC potential. We generated a searchable HSC DNA methylation database incorporating available datasets and present a truncated list of methylation sites associated with changes in HSC function for prioritization to target for resetting the age-associated loss of HSC potential.

Keywords: DNA methylation; Gadd45b; aging; epigenetics; hematopoietic stem cell; searchable DNA methylation database

DOI: https://doi.org/10.1111/acel.70453

Nat Commun. 2026 Mar 18.

Chromatin reorganization drives overexpression of a Btaf1 variant underpinning hematopoietic aging.

Le Zong, Bongsoo Park, Yaqiang Cao, Fei Ma, Ferda Tekin-Turhan, Wakako Kuribayashi, Keji Zhao, Isabel Beerman.

Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we perform epigenetic profiling in male mice to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We identify a looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs which is accompanied by overexpression of a shorter variant of Btaf1 (nBtaf1). Mechanistically, elevated expression of nBtaf1 drives the aging-associated overexpression of HSC and megakaryocyte progenitor (MkP) signature genes via regulating TBP binding at their promoters, which contributes to HSC expansion and elevated MkP production in aged mice. ShRNA-mediated knockdown of nBtaf1 restores a younger HSC transcriptome and specifically represses aging-associated HSC expansion and elevated MkP production. In summary, our data provide high resolution analysis of a dysregulated HSC aging epigenome and reveal a Btaf1 variant that drives HSC aging phenotypes in mice.

DOI: https://doi.org/10.1038/s41467-026-70787-4

Mutat Res Rev Mutat Res. 2026 Mar 17. pii: S1383-5742(26)00003-7. [Epub ahead of print]797 108587

Mitochondrial DNA: Bridging cellular senescence and chronic inflammation in aging and beyond.

Shimeng Wang, Fanglong Wu, Hongmei Zhou.

Aging is a progressive and irreversible physiological process driven by a complex network of interrelated molecular and cellular mechanisms. Among these, cellular senescence and chronic inflammation, as two core hallmarks of aging, are interlinked and jointly promote the development and progression of aging. However, the precise molecular crosstalk between these two processes remains unclarified. Mitochondrial DNA (mtDNA), as the only cytoplasmic DNA, has recently emerged as a pivotal "bridge" linking cellular senescence and chronic inflammation through various mechanisms. Anchored on the unique characteristics of mtDNA, this review systematically elucidates its central roles in mitochondrial dysfunction and oxidative stress, with a particular emphasis on the dynamic changes of mtDNA within the cytosol and extracellular space that construct and amplify the cellular "inflammation-senescence" coupling network. Furthermore, we propose a conceptual framework linking mtDNA mutation/damage to the cellular senescence and the propagation of chronic inflammation. Finally, we discuss the therapeutic potential of targeting mtDNA dynamics and highlight key challenges and future directions in this emerging field, offering novel insights for mitigating aging and age-related diseases.

Keywords: Aging-related diseases; Cellular senescence; Chronic inflammation; Mitochondrial DNA; Therapeutic intervention

DOI: https://doi.org/10.1016/j.mrrev.2026.108587

Redox Biol. 2026 Mar 10. pii: S2213-2317(26)00119-9. [Epub ahead of print]92 104121

Excessive ER-mitochondria coupling: A DRP1-driven mechanism underlying mitochondrial dysfunction and impaired autophagy in stress-induced depression-like behavior in mice.

Jia-Rui Zhang, Jia-Yan Zhang, Qing-Ya Sun, Chang Chen, Jing-Wei Yang, Nan Cheng, Zi-Wen Guo, Ruo-Nan Shuang, Wei Gu, Meng-Ying Zhai, Jin-Ao Duan, Wei-Wei Tao.

BACKGROUND: Depression is a common psychiatric disorder characterized by heightened stress exposure and disruptions in neuronal signaling. Growing evidence suggests that mitochondrial dysfunction contributes to its pathophysiology. In particular, mitochondrial dynamics regulated by Dnm1l/Drp1 are critical for neuronal homeostasis, and their dysregulation may lead to cellular impairment. Additionally, mitochondrial-endoplasmic reticulum contact sites (MERCs) are crucial for maintaining cellular function and require precise regulation. However, the role of Drp1 in modulating MERC structure and function in the context of depression remains unclear.
METHODS: We quantified protein changes via 4D-FastDIA proteomics. MERC alterations were examined using transmission electron microscopy (TEM) and proximity ligation assay (PLA). Mitochondrial metabolism was assessed with the Seahorse XF Analyzer. Autophagy was visualized through tyramine signal amplification and Imaris-based 3D reconstruction. The causal relationship was tested using Vglut2-Cre mice combined with specific flox-virus mediated Drp1 manipulation and pharmacological inhibition of autophagy. Depression-like behaviors were evaluated after chronic social defeat stress (CSDS).
RESULTS: Drp1 activation disrupts mitochondrial-endoplasmic reticulum contact sites (MERCs), leading to mitochondrial dysfunction and impaired autophagy, and ultimately promoting depressive-like behaviors. Inhibiting the MERC tethering protein GRP75 or enhancing mitophagy pharmacologically alleviated these neuronal and behavioral deficits. These findings identify Drp1-mediated MERC disruption as a key mechanism in depression and suggest therapeutic strategies targeting MERC integrity and autophagy.
CONCLUSION: Our results provide novel mechanistic evidence that Drp1-mediated dysfunction at MERCs and impaired mitochondrial quality control contribute to the pathogenesis of depression. These findings underscore the importance of endoplasmic reticulum-mitochondrial crosstalk in depression and suggest potential therapeutic targets for modulating cellular resilience in stress-related disorders.

Keywords: Depression; Mitochondrial-endoplasmic reticulum contact sites (MERCs); Mitochondrion; Mitophagy; drp1

DOI: https://doi.org/10.1016/j.redox.2026.104121