bims-tofagi 2025-10-19 papers

Issue of 2025–10–19
two papers selected by
Michele Frison, University of Cambridge

J Cell Mol Med. 2025 Oct;29(19): e70704

BNIP3L/BNIP3-Mediated Mitophagy Contributes to the Maintenance of Ovarian Cancer Stem Cells.

Na Li, Tejinder Pal Khaket, Yajing Yang, Linzhou Wang, Shurui Cai, Aidan Li, Elsa Wani, Jessica Miao, Nan Zhang, Qingfei Zheng, Junran Zhang, Xuefeng Liu, Selvendiran Karuppaiyah, Dehua Pei, Qi-En Wang.

Ovarian cancer remains the most lethal gynaecological malignancy, with tumour recurrence and chemoresistance posing significant therapeutic challenges. Emerging evidence suggests that cancer stem cells (CSCs), a rare subpopulation within tumours with self-renewal and differentiation capacities, contribute to these hurdles. Therefore, elucidating the mechanisms that sustain CSCs is critical for improving treatment strategies. Mitophagy, a selective process for eliminating damaged mitochondria, plays a key role in maintaining cellular homeostasis, including CSC survival. Our study demonstrates that ovarian CSCs exhibit enhanced mitophagy, accompanied by elevated expression of the mitochondrial outer membrane receptors BNIP3 and BNIP3L. Knockdown of BNIP3 or BNIP3L significantly reduces mitophagy and impairs CSC self-renewal, indicating that receptor-mediated mitophagy is essential for CSC maintenance. Mechanistically, we identify that hyperactivated NF-κB signalling drives the upregulation of BNIP3 and BNIP3L in ovarian CSCs. Inhibition of NF-κB signalling, either via p65 knockdown or pharmacological inhibitors, effectively suppresses mitophagy. Furthermore, we demonstrate that elevated DNA-PK expression contributes to the constitutive activation of NF-κB signalling, thereby promoting mitophagy in ovarian CSCs. In summary, our findings establish that BNIP3/BNIP3L-mediated mitophagy, driven by DNA-PK-dependent NF-κB hyperactivation, is essential for CSC maintenance. Targeting the DNA-PK/NF-κB/BNIP3L-BNIP3 axis to disrupt mitochondrial quality control in CSCs represents a promising therapeutic strategy to prevent ovarian cancer recurrence and metastasis.

Keywords: BNIP3; BNIP3L; DNA‐PK; NF‐κB; cancer stem cells; mitophagy; ovarian cancer

DOI: https://doi.org/10.1111/jcmm.70704

EMBO Mol Med. 2025 Oct 15.

Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy.

Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.

Keywords: Amyotrophic Lateral Sclerosis; Drug Screening; Isoginkgetin; Mitophagy; PINK1-Parkin

DOI: https://doi.org/10.1038/s44321-025-00323-2