The role of mitochondrial dysfunction in sepsis-induced multi-organ failure

Abstract

An important role for bioenergetic dysfunction is increasingly emerging to potentially explain the paradox of clinical and biochemical organ failure in sepsis yet minimal cell death, maintained tissue oxygenation and recovery in survivors. Associations are well-recognized between the degree of mitochondrial dysfunction and outcomes. While this does not confirm cause-and-effect, it does nevertheless suggest a new route for therapeutic intervention focused on either mitochondrial protection or acceleration of the recovery process through stimulation of mitochondrial biogenesis (new protein turnover). This is particularly pertinent in light of the multiple trial failures related to immunomodulatory therapies. This overview will provide insights into mitochondrial biology, the relevance to sepsis, and therapeutic opportunities that possibly emerge.

Keywords: biogenesis; mitochondria; mitophagy; multi-organ failure; nitric oxide; reactive oxygen species; sepsis.

Figure 1. Sources of ATP production. Glucose is metabolized to pyruvate via the glycolytic pathway. Pyruvate (and free fatty acids) enter the mitochondria where they are converted to acetyl CoA. This enters the Krebs cycle that, via NADH and FADH₂, donates electrons to Complexes I and II of the electron transport chain, respectively. The electrons pass down the chain to Complex III and thence to Complex IV, where oxygen is the terminal electron acceptor. Protons cross the mitochondrial membrane and, in so doing, create an electrochemical gradient to enable ATP synthase to generate ATP from ADP. The ATP is then transported to the cytosol to fuel energy-requiring cellular processes. A relatively small amount of ATP is also produced by glycolysis and the Krebs cycle.