2. Academic Validation
  3. Mitochondrial retrograde signaling initiates HIF-1α/BNIP3/NIX-mediated mitophagy in Tibetan high-altitude adaptation

Mitochondrial retrograde signaling initiates HIF-1α/BNIP3/NIX-mediated mitophagy in Tibetan high-altitude adaptation

  • Cell Death Discov. 2026 Jan 6;12(1):81. doi: 10.1038/s41420-025-02933-8.
Yang Wei # 1,  Dayan Sun # 1 2,  Fei Wu # 1,  Shixuan Zhang 1,  Bowen Cai 1,  Yanyun Ma 3,  Hongxiang Zheng 1,  Xiangguang Shi 1 4,  Yi Li 1,  Shiguan Le 1,  Xiang Zhou 1,  Li Jin 5 6,  Jiucun Wang 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China.
  • 2 Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
  • 3 Academy for Engineering & Technology, Fudan University, Shanghai, 200433, China.
  • 4 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
  • 5 State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China. [email protected].
  • 6 Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, 210042, China. [email protected].
  • 7 State Key Laboratory of Genetic and Development of Complex Phenotypes, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China. [email protected].
  • 8 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, China. [email protected].
  • 9 Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, 210042, China. [email protected].
  • # Contributed equally.
PMID: 41490888 DOI: 10.1038/s41420-025-02933-8
Abstract

Genome-wide studies have identified the nuclear gene EPAS1 and the mitochondrial M9a haplogroup as pivotal contributors to hypoxia adaptation in Tibetans. However, the interaction between these two genetic components is not yet clear. In this study, we demonstrate that cells harboring the Tibetan-specific M9a haplogroup with downregulated EPAS1 (M9a+shEPAS1) exhibit enhanced cellular function under hypoxic conditions. These cells display improved mitochondrial function and proliferation, alongside reduced Apoptosis and mtDNA-mediated inflammation, driven by the activation of HIF-1α-BNIP3/NIX-mediated Mitophagy and an increase in Reactive Oxygen Species (ROS) levels. Furthermore, treatment with N-acetylcysteine (NAC), PX-478, or Mdivi-1 significantly attenuated BNIP3/NIX-mediated Mitophagy, leading to an aggravation of mtDNA-mediated inflammation and Apoptosis in M9a+shEPAS1 cells during hypoxia. This study first reveals that ROS-driven HIF-1α-BNIP3/NIX-mediated Mitophagy mitigates hypoxia-induced inflammation and Apoptosis, contributing to the enhanced hypoxia adaptation observed in Tibetans. HIF-1α-BNIP3/NIX-mediated Mitophagy may offer potential therapeutic targets for high-altitude illnesses by regulating cellular energy metabolism and inflammation.

Figures
Products