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

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.