bims-tofagi 2026-01-04 papers

Issue of 2026–01–04
two papers selected by
Michele Frison, University of Cambridge

Aging Cell. 2026 Jan;25(1): e70347

PRKN-Mediated Ubiquitin-Proteasome Degradation of METTL3 Promotes Cellular Senescence.

Liping Chen, Canfeng Zhang, Yuanlong Ge, Haoxian Zhou, Shenglong Yang, Wenjing Wei, Qinghua Zhou, Kaizhen Xiao, Guangyu Huang, Xiaocui Li, Jia Wang, Jinping Zheng, Ronghe Gu, Zhenyu Ju, Shu Wu.

N6-methyladenosine (m6A) methylation, a dynamic and reversible modification of eukaryotic mRNAs, plays critical roles in diverse cellular processes. Although METTL3-mediated m6A deposition has been implicated in cellular senescence, the mechanisms controlling METTL3 stability and activity during senescence remain poorly defined. Here, we demonstrate that both m6A levels and METTL3 protein abundance are significantly reduced in replication-induced and stress-induced senescence models. METTL3 depletion promotes senescence by inducing telomere dysfunction via diminished expression of shelterin components TRF2 and POT1. Mechanistically, we identify PRKN (Parkin) as a senescence-associated E3 ubiquitin ligase that promotes METTL3 proteasomal degradation through K48-linked polyubiquitination at lysine 164. Genetic PRKN inhibition in pre-senescent cells rescues METTL3 expression, restores TRF2/POT1 levels, reduces telomere dysfunction-induced foci (TIFs), and attenuates senescence-associated β-galactosidase (SA-β-gal) activity. Crucially, PRKN overexpression accelerates telomere dysfunction and senescence in wild-type METTL3-expressing cells but not in cells expressing the ubiquitination-resistant K164R METTL3 mutant. Our findings establish METTL3 ubiquitination as a pivotal regulator of telomere integrity and senescence progression, unveiling a therapeutic target for age-related pathologies.

Keywords: METTL3; PRKN; m6A; senescence; telomere

DOI: https://doi.org/10.1111/acel.70347

Stem Cell Reports. 2025 Dec 26. pii: S2213-6711(25)00355-8. [Epub ahead of print] 102751

Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.

Ting Song, Yang Song, Hong Zhang, Zhiyuan Hu, Fangkui Yin, Maojun Jiang, Yanxin Zhang, Ziqian Wang, Zhichao Zhang.

In chronic myeloid leukemia (CML), disease persistence in patients is maintained by leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance. Autophagy has been proposed as a potential therapy to eradicate CML LSCs. Here, using a small-molecule inhibitor of Hsp70 (heat shock protein 70)-Bim (Bcl-2-interacting mediator of cell death) interaction, S1-10, we demonstrate that Hsp70-Bim is a target for CML stemness maintenance. Hsp70-Bim is driven by Bcr-Abl and mediates particularly stronger mitophagy in CML LSCs than differentiated CML cells and HSCs. The more selective mitophagy regulation of Hsp70-Bim than ULK1 (unc-51-like autophagy activating kinase 1) is illustrated. Pharmacological inhibition of Hsp70-Bim blocks mitophagy, leading to the differentiation of CML LSCs, loss of quiescence, and loss of LSC self-renewal potential. In the patient-derived xenograft (PDX) CML models, S1g-10 reduces the number of LSCs by more than 80% after two weeks of injection, without obvious toxicity on normal red blood cells.

Keywords: Hsp70-Bim; chronic myeloid leukemia; leukemia stem cells; mitophagy; tyrosine kinase inhibitor

DOI: https://doi.org/10.1016/j.stemcr.2025.102751