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The world highest and largest altitude area is called the Qinghai-Tibetan plateau (QTB), 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 stressors at high altitude 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 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 haemoglobin concentration in high altitude mammals for adaptation. The yak is a much more ancient mammal which has existed
on QTB 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 hypoxic reaction of molecular mechanisms. (Vague) 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-altitude, pregnancies yield a low birth weight ∼100 g per1000 m of the climb. (Vague) It may involve
variation in the events of energy-demanding, 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, might be adaptive in beginning but severe later.