Alternative oxidase expression in mtDNA mutator mice improves blood phenotype but enhances inflammatory and stress responses in skeletal muscle

Energetic insufficiency, excess production of reactive oxygen species (ROS) and aberrant signalling partially account for the diverse pathology of mitochondrial diseases. Whether interventions affecting ROS, a regulator of stem-cell pools, could modify somatic stem-cell homeostasis remains unknown. Previous data from mitochondrial DNA (mtDNA) mutator mice showed that increased ROS leads to oxidative damage in erythroid progenitors, causing lifespan-limiting anemia. Also unclear is how ROS-targeted interventions affect terminally differentiated tissues. Here, we set out to test in mtDNA mutator mice how ubiquitous expression of the Ciona intestinalis alternative oxidase (AOX), which attenuates ROS production, affects murine stem-cell pools. We found that AOX does not affect neural stem cells but delays the progression of mutator-driven anemia. Furthermore, when combined with the mutator, AOX potentiates mitochondrial stress and inflammatory responses in skeletal muscle. These differential cell-type-specific findings demonstrate that AOX expression is not a global panacea for the cure of mitochondrial dysfunction. ROS attenuation needs to be carefully studied regarding specific underlying defects before AOX can be safely used in therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/530968v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@17bfd6org.highwire.dtl.DTLVardef@1338f2aorg.highwire.dtl.DTLVardef@1fc269borg.highwire.dtl.DTLVardef@14abc5e_HPS_FORMAT_FIGEXP M_FIG C_FIG