The Oxygen Cascade from Atmosphere to Mitochondria as a Tool to Understand the (Mal)adaptation to Hypoxia

Hypoxia is a life-threatening challenge for about 1% of the world population, as well as a contributor to high morbidity and mortality scores in patients affected by various cardiopulmonary, hematological, and circulatory diseases. However, the adaptation to hypoxia represents a failure for a relevant portion of the cases as the pathways of potential adaptation often conflict with well-being and generate diseases that in certain areas of the world still afflict up to one-third of the populations living at altitude. To help understand the mechanisms of adaptation and maladaptation, this review examines the various steps of the oxygen cascade from the atmosphere to the mitochondria distinguishing the patterns related to physiological (i.e., due to altitude) and pathological (i.e., due to a pre-existing disease) hypoxia. The aim is to assess the ability of humans to adapt to hypoxia in a multidisciplinary approach that correlates the function of genes, molecules, and cells with the physiologic and pathological outcomes. We conclude that, in most cases, it is not hypoxia by itself that generates diseases, but rather the attempts to adapt to the hypoxia condition. This underlies the paradigm shift that when adaptation to hypoxia becomes excessive, it translates into maladaptation.