The world's highest and largest altitude area is called the Qinghai-Tibetan plateau QTP,
which harbors unique animal and plant species. Mammals that inhabit the higher altitude regions
have adapted well to the hypoxic conditions. One of the main stressor at high altitudes is hypoxia.
Metabolic responses to hypoxia play important roles in cell survival strategies and some diseases.
However, the homeostatic alterations that equilibrate variations in the demand and supply of energy
to maintain organismal function in a prolonged low O2 environment persist partly in understood,
making it problematic to differentiate adaptive from maladaptive responses in hypoxia. Tibetans
and yaks are two perfect examples innate to the plateau for high altitude adaptation. By the scan of
the whole-genome, EPAS1 and EGLN1 were identified as key genes associated with sustained hemoglobin
concentration in high altitude mammals for adaptation. The yak is a much more ancient
mammal that has existed on QTP longer than humans. It is, therefore, possible that natural selection
represented a diverse group of genes/pathways in yaks. Physiological characteristics are extremely
informative in revealing molecular networks associated with inherited adaptation, in addition
to the whole-genome adaptive changes at the DNA sequence level. Gene-expression can be
changed by a variety of signals originating from the environment, and hypoxia is the main factor
amongst them. The hypoxia-inducible factors (HIF-1α and EPAS1/HIF-2α) are the main regulators
of oxygen in homeostasis, which play a role as maestro regulators of adaptation in the hypoxic reaction
of molecular mechanisms. The basis of this review is to present recent information regarding
the molecular mechanism involved in hypoxia that regulates candidate genes and proteins. Many
transcriptional responses toward hypoxia are facilitated by HIFs that change the number of gene expressions
and help in angiogenesis, erythropoiesis, metabolic reprogramming, and metastasis. HIFs
also activate several signals highlighting a strong association between hypoxia, the misfolded proteins’
accumulation in the endoplasmic reticulum in stress, and activation of Unfolded Protein Response
(UPR). It was observed that at high-altitudes, pregnancies yield a low birth weight 100 g
per1000 m of the climb. It may involve variation in the events of energy-demand, like protein synthesis.
Prolonged hypobaric hypoxia causes placental ER stress, which, in turn, moderates protein
synthesis and reduces proliferation. Further, Cardiac hypertrophy by cytosolic Ca2+ raises and
Ca2+/calmodulin, calcineurin stimulation, NF-AT3 pathway might be caused by an imbalance in
Sarcoplasmic reticulum ER Ca2+, which might be adaptive in the beginning but severe later on.