Mitochondria: a multimodal hub of hypoxia tolerance

Decreased oxygen availability impairs cellular energy production and, without a coordinated and matched decrease in energy consumption, cellular and whole organism death rapidly ensues. Of particular interest are mechanisms that protect brain from low oxygen injury, as this organ is not only the most sensitive to hypoxia, but must also remain active and functional during low oxygen stress. As a result of natural selective pressures, some species have evolved molecular and physiological mechanisms to tolerate prolonged hypoxia with no apparent detriment. Among these mechanisms are a handful of responses that are essential for hypoxia tolerance, including (i) sensors that detect changes in oxygen availability and initiate protective responses; (ii) mechanisms of energy conservation; (iii) maintenance of basic brain function; and (iv) avoidance of catastrophic cell death cascades. As the study of hypoxia-tolerant brain progresses, it is becoming increasingly apparent that mitochondria play a central role in regulating all of these critical mechanisms. Furthermore, modulation of mitochondrial function to mimic endogenous neuroprotective mechanisms found in hypoxia-tolerant species confers protection against otherwise lethal hypoxic stresses in hypoxia-intolerant organs and organisms. Therefore, lessons gleaned from the investigation of endogenous mechanisms of hypoxia tolerance in hypoxia-tolerant organisms may provide insight into clinical pathologies related to low oxygen stress.