At high altitude, hypoxia-inducible factor (HIF-1α) mediates many adaptive responses. HIF-1α is normally rapidly degraded by the proteasome. Which molecular mechanism stabilizes HIF-1α during hypoxia?

• A Hypoxia activates AMPK, which phosphorylates HIF-1α to prevent its ubiquitination
• B Reduced O₂ availability inhibits prolyl hydroxylase domain (PHD) enzymes, preventing hydroxylation of HIF-1α proline residues, thereby blocking VHL-mediated ubiquitination and proteasomal degradation ✓
• C Reactive oxygen species (ROS) from hypoxic mitochondria directly cleave the VHL-HIF binding domain
• D Hypoxia induces p53 expression, which competes with HIF-1α for VHL binding sites

Explanation

Under normoxia, PHD1/2/3 (prolyl hydroxylase domain proteins) use O₂ and α-ketoglutarate as co-substrates to hydroxylate specific proline residues (Pro402 and Pro564) on HIF-1α. Hydroxylated HIF-1α is recognized by VHL (von Hippel-Lindau E3 ubiquitin ligase complex), poly-ubiquitinated, and degraded by the 26S proteasome (half-life ~5 minutes in normoxia). In hypoxia, PHDs lose their O₂ substrate → HIF-1α is unhydroxylated → escapes VHL recognition → accumulates → dimerizes with HIF-1β → activates HRE (hypoxia response element)-containing genes: EPO, VEGF, GLUT1, glycolytic enzymes. VHL mutations in clear cell RCC cause constitutive HIF activation mimicking permanent hypoxia.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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