Alternative oxidase AOX combats bacterial sepsis

Submitted on Fri, 09/23/2016 - 12:08

In a paper just published in Cell, university researcher Marten Szibor and Professor Howy Jacobs from FinMIT Centre of Excellence have demonstrated the surprising potential of the mitochondrial ‘alternative oxidase’ (AOX) in combating the runaway inflammatory process that leads to multiple organ failure and eventual death, in bacterial sepsis.

The paper, a collaboration between research teams in Ireland, the UK, the US and Germany, as well as Finland, deals with the wider issue of how mitochondria participate in the signalling process that leads to the activation of macrophages, cells that are one of the most important front-line components of the immune system. When stimulated by LPS, a common chemical constituent of the outer envelope of bacteria, macrophages were found to undergo a reprogramming of metabolism in which mitochondria switch from being generators of cellular energy in the form of ATP to the production of oxygen radicals (ROS), initiating a cascade of pro-inflammatory signals. A number of different treatments which limit ROS production can counteract this process. Amongst them is the expression of AOX, which Professor Jacobs’ group have been studying for a number of years, because of its ability to buffer a variety of pathological stresses in mitochondria.

AOX is not found naturally in mammals, so the group have turned to the sea-squirt Ciona as a source. Remarkably, the AOX gene from this species is fully functional when expressed in human cells or model organisms like fruit-flies or mice. It acts as a kind of by-pass of the mitochondrial energy system, when the latter isn’t fully functional due to chemical damage, toxins, genetic errors or overload. Under normal conditions, AOX seems to have no effect on cellular processes, yet it acts as a kind of safety-valve when the mitochondria become stressed. AOX thus blocks the lethal inflammatory process that occurs in sepsis, because it relieves the build-up of metabolic intermediates that otherwise lead to excessive ROS production.

More people die of sepsis than of cancer. So anything that improves our understanding of how it develops and how to combat it, should have dramatic life-saving implications. It’s obviously far too soon to say whether AOX could be used as an actual therapy for sepsis, and if so, how best to deliver it. But equally, using the knowledge obtained in this project may lead to simpler, ‘chemical’ ways of producing a similar outcome and saving many lives.

FinMIT is a research cluster involving teams in University of Tampere and Helsinki, aiming at an understanding of how mitochondria are involved in disease and how this knowledge can be used in the future to help patients.

Evanna L. Mills, Beth Kelly, Angela Logan, Ana S.H. Costa, Mukund Varma, Clare E. Bryant,  Panagiotis Tourlomousis,  J. Henry M. Däbritz, Eyal Gottlieb, Isabel Latorre,  Sinéad C. Corr,  Gavin McManus,  Dylan Ryan,  Howard T. Jacobs, Marten Szibor, Ramnik J. Xavier, Thomas Braun, Christian Frezza, Michael P. Murphy, Luke A. O’Neill: Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell.

http://dx.doi.org/10.1016/j.cell.2016.08.064

For more information, please contact:
Professor Howy Jacobs, Tel +358 50 341 2894, howard.jacobs@helsinki.fi