JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

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

Author(s): Mengchen ZHANG^1, ², Yi LI^1, ², Huiqi LIN³, Tianfu YU^1, ², Fangyuan XIA^1, ², Mahanand CHATOO^1, ², Kexin LI⁴, Honghao YU⁵, Eviatar NEVO⁶, Jizeng DU², Yang ZHAO³, Xuequn CHEN^1, ²
Affiliation(s): ¹Department of Neurology of The Second Affiliated Hospital, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310016, China ²NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China ³Department of Physiology and Department of Hepatobiliary and Pancreatic Surgery of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China ⁴State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, College of Ecology, Lanzhou University, Lanzhou 730000, China ⁵College of Biotechnology, Guilin Medical University, Guilin 541004, China ⁶Institute of Evolution, University of Haifa, Haifa 31905, Israel
Corresponding email(s): Xuequn CHEN, chewyg@zju.edu.cn Yang ZHAO, yang.zhao@zju.edu.cn
Key Words: MDM2; Plateau zokor; Apoptosis; Adaptation; Extreme environment

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Mengchen ZHANG^1,², Yi LI^1,², Huiqi LIN³, Tianfu YU^1,², Fangyuan XIA^1,², Mahanand CHATOO^1,², Kexin LI⁴, Honghao YU⁵, Eviatar NEVO⁶, Jizeng DU², Yang ZHAO³, Xuequn CHEN^1,². MDM2/X mediate reduced apoptosis in plateau zokor: a mechanism of high-altitude adaptation[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2500281

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author="Mengchen ZHANG^1,², Yi LI^1,², Huiqi LIN³, Tianfu YU^1,², Fangyuan XIA^1,², Mahanand CHATOO^1,², Kexin LI⁴, Honghao YU⁵, Eviatar NEVO⁶, Jizeng DU², Yang ZHAO³, Xuequn CHEN^1,²",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500281"
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%J Journal of Zhejiang University SCIENCE B
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doi="https://doi.org/10.1631/jzus.B2500281"

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Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: MDM2 (Murine double minute 2) and MDMX (Murine double minute 4) are critical for the regulation of p53 function and apoptosis. This study compares the Mdm2/x gene sequences and functional variations of subterranean zokors in high plateaus and loess plateaus. The findings reveal the molecular mechanisms behind how these species' 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 (M.b., plateau zokor) and Myospalax cansus (M.c., Gansu zokor), and reconstructed phylogenetic trees for a series of rodents and mammals of subterranean species and the aboveground lab rat, as well as humans. We found that MDM2/X of M.b. and M.c. are involved in the low apoptosis rate dependent on p53, and the variations of phosphorylation sites in the C-terminal 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.

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