MDM2/X mediates reduced apoptosis in the plateau zokor: a mechanism of high-altitude adaptation

Abstract

Murine double minute 2 (MDM2) and murine double minute 4 (MDMX) are critical for the regulation of tumor protein 53 (p53) function and apoptosis. This study compares the Mdm2 / x gene sequences and functional variations of subterranean zokors from the High Plateau and the Loess Plateau. The findings reveal the molecular mechanisms by which Mdm2 / x variations drive adaptation to extremely high-altitude conditions—including low oxygen, cold temperatures, and perpetual darkness in underground environments. We cloned and analyzed Mdm2 / x sequences from two distinct ecological groups of subterranean rodents, Myospalax baileyi (plateau zokor) and Myospalax cansus (Gansu zokor), and reconstructed phylogenetic trees for a series of subterranean rodents and mammals, as well as the aboveground laboratory rat and humans. We found that MDM2/X in M. baileyi and M. cansus are involved in the p53-dependent low apoptosis rate, and the variations of phosphorylation sites at the C-terminus of MDM2 contribute to upregulation of p53 transcription and protein expression. We propose that gene evolutionary mechanisms enable survival under these severe combined pressures, and believe that our findings provide critical insight into how genetic modifications drive physiological resilience in Earth’s most challenging ecosystems.