Impact of mitochondrial reactive oxygen species (ROS) on systemic inflammatory response syndrom (SIRS)- or sepsis-induced organ failure

Excessive systemic inflammation in trauma patients often leads to multiple organ failure and death. However, the mechanisms underlying this process are poorly understood. The aim of this study was to investigate the interplay between inflammatory mediators and mitochondria, which are the main producers of cellular energy (adenosine triphosphate (ATP)), in order to understand the exact role of mitochondria in this process.

We found that elevated levels of mitochondrial reactive oxygen species (mtROS) and nitric oxide (NO), synthesized by inducible nitric oxide synthase (iNOS), form a feed-forward loop, which substantially contributes to the development of liver failure upon acute inflammation. This iNOS-mtROS cycle accelerates liver failure by activating intracellular pathological signaling cascades and the induction of oxidative stress, causing damage to biomembranes and releasing tissue damage markers into the blood.

Interestingly, we could show that the application of mitochondria-targeted antioxidants as well as NOS inhibitors interrupts the iNOS-mtROS cycle and reverses liver dysfunction. This suggests a possibility to inhibit the iNOS-mtROS cycle and might be a specific approach for development of therapeutics for the treatment of patients with sepsis/ systemic inflammatory response syndrome.
For detailed information, see “Vicious inducible nitric oxide synthase-mitochondrial reactive oxygen species cycle accelerates inflammatory response and causes liver injury in rats”, Weidinger et al., Antioxid. Redox. Signal., 2015 Mar 1;22(7):572-86. doi: 10.1089/ars.2014.5996..

We are currently working on further questions regarding mitochondria-targeted antioxidants. More recently, we have shown that their effect can also be deleterious, because they can impair bactericidal activity of macrophages.