Autophagy, the First Step Towards Recovery From Critical Illness*

Abstract

S trong evidence links pathological changes at the cell and tissue level with organ failures and mortality in the context of systemic inflammation during critical illness (1). Understanding the proximal mediators of these cytopathic events, including the systemic and regional effects of various proinflammatory mediators, is a topic of active investigation, and even less is known about the mechanisms regulating cell and organ recovery. In this context, mitochondria are well-recognized targets of injury during systemic inflammation, and impaired mitochondrial function has been linked to organ failures and death. Furthermore, restoration of normally functioning mitochondrial populations is a hallmark of survivors of critical illness (2, 3).In response to acute cell stress, certain cytoprotective measures are initiated. With respect to mitochondria, senescent or damaged mitochondria are selectively removed through a process of autodigestion (autolysis) (4) and subsequent lysosomal clearance (autophagy), which is often referred to as "mitophagy." A full description of mitophagy and its role in cellular homeostasis is beyond the scope of this editorial, but the interested reader is referred to a review by Ashrafi and Schwarz (5). In essence, autophagy serves to match the energy needs of the cell and perform "quality control" by clearing mitochondria that are no longer fully functional. Given that damaged mitochondria can produce potentially toxic byproducts (e.g., reactive oxygen species) or release proapoptotic proteins, removal of damaged mitochondria can prevent further cytopathic damage or even avert cell death (5). In this regard, recent studies indicate that mitophagy plays an important role in selectively removing damaged mitochondria during the acute phase of sepsis (6, 7). Although autophagy is presumed to be protective under these circumstances, it is known that excessive autophagy can lead to cell death. Thus, autophagy, particularly involving mitochondria, can be viewed as a proverbial "twoedged sword" (8).Among the important systemic regulators of autophagy, the inhibitory effects of insulin are well documented (9); however, the effects of hyperglycemia are less clear. Hyperinsulinemia and hyperglycemia (reflecting insulin resistance) are common manifestations of critical illness, and normalization of hyperglycemia was previously demonstrated to correlate with enhanced autophagy in critically ill humans (10). To further clarify the role of autophagy during acute illness, the study by Gunst et al (11), in this issue of Critical Care Medicine, sought to determine if prevention of hyperglycemia leads to enhanced autophagy (particularly mitophagy), less organ damage, and improved mortality in the setting of critical illness. To this end, a rabbit model of third-degree burn injury, which is associated with significant systemic organ damage and mortality (56%), was modified to achieve hyperinsulinemia with hyperglycemia or hyperinsulinemia with normoglycemia. As such, the effects of hyperinsulinemia could be iso...

Treatment of Mitochondrial Disorders

“…Restoration of mitochondrial function may be an important step in recovery from critical illness [89, 90]. Patients with a baseline impairment in mitochondrial function are thus at particular risk for decompensation in the setting of an acute illness.…”

Development and current use of parenteral nutrition in critical care – an opinion paper

“…Recent research has focused on autophagy, which belongs to the healing process as removal of mitochondria damaged during the acute phase of sepsis. This mechanism is a two-edged sword, however, which may cause cell death [ 45 ]. Insulin is a well-documented inhibitor of autophagy [ 46 ].…”