Mind the mitochondria!
Safeguarding an adequate oxygen transport to organs and tissues is a prime goal in the care for critically ill patients. Over the last two decades it has become clear that in certain pathophysiological circumstances macrocirculatory derailment is followed, or accompanied, by microcirculatory dysfunction. Resuscitation strategies to restore and optimize blood flow to organs are based on the idea that restoring oxygen supply will re-establish aerobic metabolism and lead to “healthy parenchymal cells”. However, mitochondrial damage and subsequent dysfunction, or cellular adaptation to hypoxia, might attenuate or even counterbalance the positive effects of resuscitation on the cellular level. In this short review we will address mitochondrial function and adaptation, causes of mitochondrial dysfunction, the concept of cytopathic hypoxia, (loss of) hemodynamic coherence and ways to assess aspects of mitochondrial function in patients. Mitochondria are the primary consumers of oxygen and the ultimate destination of approximately 98% of oxygen reaching our tissue cells. Most of the oxygen is used for energy production by oxidative phosphorylation, but a small amount is used for generating reactive oxygen species and heat generation. While adenosine triphosphate (ATP) production is the best-known function of mitochondria, they also play key roles in calcium homeostasis and cell-death mechanisms. Oxidative phosphorylation has a very high affinity for oxygen and functions well at very low oxygen levels. However, cellular respiration does adapt to changes in oxygen availability at physiological levels, a mechanism known as “oxygen conformance”. Oxygen conformance, mitochondrial damage by certain hits (e.g., toxins and medication), mitochondrial dysfunction and autonomic metabolic reprogramming are factors that could contribute to what is known as “cytopathic hypoxia”. This concept describes insufficient oxygen metabolism in cells despite sufficient oxygen delivery in sepsis. Altered cellular oxygen utilization and thus reduced oxygen demand could in itself cause decreased microcirculatory blood flow, making microcirculatory dysfunction in sepsis under some circumstances a possible epiphenomenon. Resuscitation and forced restoration of microcirculatory flow could lead to relative hyperoxia, and be counterproductive by increasing reactive oxygen production and intervening with protective adaptation mechanisms. The complex pathophysiology of a critically ill patient, especially in severe sepsis and septic shock, requires a multilevel approach. In understanding the interplay between macrocirculation, microcirculation, and parenchymal cells the mitochondria are key players that should not be overlooked. Progress is being made in technologies to assess aspects of mitochondrial function at the bedside, for example direct measurement of mitochondrial oxygen tension and oxygen consumption.