Bench-to-bedside review: potential strategies to protect or reverse mitochondrial dysfunction in sepsis-induced organ failure

Alessandro Protti, Mervyn Singer, Alessandro Protti, Mervyn Singer

Abstract

The pathogenesis of sepsis-induced multiple organ failure may crucially depend on the development of mitochondrial dysfunction and consequent cellular energetic failure. According to this hypothesis, interventions aimed at preventing or reversing mitochondrial damage may have major clinical relevance, although the timing of such interventions will be critical to both ensuring benefit and avoiding harm. Early correction of tissue hypoxia, strict control of glycaemia, and modulation of oxidative and nitrosative stress may afford protection during the initial, acute systemic inflammatory response. The regulated induction of a hypometabolic state resembling hibernation may protect the cells from dying once energy failure has developed, allowing the possibility of functional recovery. Repair of damaged organelles through stimulation of mitochondrial biogenesis and reactivation of cellular metabolism may accelerate resolution of the multiple organ failure syndrome.

Figures

Figure 1
Figure 1
Schematic representation of oxidative phosphorylation within the mitochondria. Electrons donated from NADH and FADH2 pass down the electron transport chain with oxygen being the terminal acceptor at complex IV. This movement of electrons results in a shift of protons across the inner mitochondrial membrane, generating the energy necessary for ATP synthase to produce ATP from ADP. FADH2, flavin adenine dinucleotide, reduced; NADH, nicotinamide adenine dinucleotide, reduced.
Figure 2
Figure 2
Hypothesized role of mitochondria in the development of MOF and subsequent recovery. Potential therapeutic interventions are illustrated at the appropriate steps. MOF, multiple organ failure.

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