Mitochondrial mechanisms of sepsis-induced organ failure

Abstract

Sepsis is the leading cause of death in medical intensive care units. Though progress has been made in the early treatment of sepsis associated with hemodynamic collapse (septic shock), little is known about the pathogenesis of delayed organ dysfunction during sepsis. A growing body of data indicates that sepsis is associated with acute changes in cell metabolism, and that mitochondria are particularly susceptible. The severity of mitochondrial pathology varies according to host and pathogen factors, and appears to correlate with loss of organ dysfunction. In this regard, low levels of cell apoptosis and mitochondrial turnover are normally observed in all metabolically active tissues; however, these homeostatic mechanisms are frequently overwhelmed during sepsis and contribute to cell and tissue pathology. Thus, a better understanding of the mechanisms regulating mitochondrial damage and repair during severe sepsis may provide new treatment options and better outcomes for this deadly disease (30-60% mortality). Herein, we present compelling evidence linking mitochondrial apoptosis pathways to sepsis-induced cell and organ failure and discuss the implications in terms of future sepsis research.

Figure 1. Pathways of apoptosis

Initiation of the extrinsic pathway begins with an extracellular death signal by a member of the tumor necrosis factor superfamily to their associated receptor. The receptor then activates caspase-8 via the Fas-associated death domain (FADD). Caspase-8 activates downstream apoptotic caspases, −3 and −7. Bid, a pro-apoptotic member of the Bcl-2 family, is also activated and thereby initiates the mitochondrial apoptotic machinery. The intrinsic pathway is activated by internal cellular damage, such as free radical generation during sepsis. Membrane permeabilization occurs either secondary to pro-apoptotic Bcl-2 proteins (Bax and Bak) associating with the outer mitochondrial membrane, this association is inhibited by Bcl-2, or though the inner mitochondrial permeability transition leading to osmotic swelling of the mitochondria and outer membrane rupture. Outer membrane permeabilization allows pro-apoptotic proteins, such has cytochrome c, to escape into the cytosol and form the apoptosome with Apaf-1, dATP, and caspase-9. The apoptosome, in turn, activates downstream caspases such as caspase-3 and −7 committing the cell to apoptosis.

Figure 2. Free radical generation during sepsis

Free electrons generated during the ETC pass through the Q-cycle (CoQ) to oxygen generating superoxide. During sepsis, mitochondrial ROS production increases and disequilibrium develops between catalase and superoxide dismutase (SOD) such that ROS are not detoxified to form water, as occurs under “normal” conditions. Instead, mitochondrial generated ROS are available to react with other oxidants, such as nitric oxide (forming peroxynitrite (ONOO⁻) and other reactive nitrogen species) or free iron (to form hydroxyl radical (OH*⁻). Ultimately, ROS modify the function of proteins and lipid membranes, and damage DNA, resulting in impaired mitochondrial function (see text).

Figure 3. Severity of mitochondrial dysfunction reflects severity of illness during sepsis

Various host factors including co-morbid diseases, age, nutritional status and genetics, together with the characteristics of the infection, including the portal of entry into the host, the pathogenicity and the size of the inoculum, determine the intensity of the inflammatory response and the hemodynamic status of the host. Inflammation, shock, and “reprogramming” of the cell related to changes in gene expression all appear to influence the functional status of mitochondria. Mitochondrial dysfunction worsens as sepsis severity increases from mild (infection and systemic inflammation without organ failure), severe sepsis (systemic inflammation with organ failure), to septic shock (systemic inflammation with hypotension). Sublethal cell stress may be associated with selective removal of a subset of irreparable mitochondrial; whereas programmed cell death occurs when cell damage exceeds a threshold sufficient to trigger the mitochondrial apoptotic pathways. Under extreme conditions, such as occurs in refractory septic shock, mitochondrial damage is overwhelming and the sudden depletion of ATP leads to cell lysis. Cell lysis, in turn, promotes a second wave of inflammation (see text).