Authors
Ning Jin, Li Zhou, Haixia Gui, Jingjing Tang, Xiaozhen Huang, Wenting Wang, Guorong Jin, Haiqin Cheng, Yuxiang Liang, Xinyi Geng, Zhiwei Peng, Hong Zhao, Zhizhen Liu, Jun Xie
Published in
Aging cell. Volume 25. Issue 10. Pages e70720.
Abstract
Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.
PMID:
42775695
Bibliographic data and abstract were imported from PubMed on 23 Sep 2026.
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