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Review
. 2023 Jan 15;24(2):1698.
doi: 10.3390/ijms24021698.

Molecular Mechanisms of High-Altitude Acclimatization

Robert T Mallet  1 , Johannes Burtscher  2   3 , Vincent Pialoux  4 , Qadar Pasha  5 , Yasmin Ahmad  6 , Grégoire P Millet  2   3 , Martin Burtscher  7   8
Affiliations
Review

Molecular Mechanisms of High-Altitude Acclimatization

Robert T Mallet et al. Int J Mol Sci. .

Abstract

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.

Keywords: acclimatization; altitude; genes; hypoxia; mitochondria; oxidative stress; redox homeostasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Time-dependent changes and related consequences of physiological responses during acclimatization to high altitude (modified from Burtscher et al., 2022 [10]). AMS, acute mountain sickness; CV, cardiovascular; CaO2, arterial oxygen content.
Figure 2
Figure 2
Parallel activation of Nrf2- and HIF-1-responsive gene programs by hypoxia.
Figure 3
Figure 3
Mitochondrial responses to hypoxic stress. Acute responses of mitochondria to hypoxia (A) that lead to beneficial (B) or detrimental (C) outcomes, depending on the hypoxic dose and cellular resilience. CI—CIV, mitochondrial respiratory complexes I—IV; CoQ, coenzyme Q; Cyt C; cytochrome C; F1F0, F1F0 ATP synthase.
Figure 4
Figure 4
Genetic influence of the two major pathways on the physiological function.
See this image and copyright information in PMC

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