OR10-001 - Altered mitochondrial ROS and metabolism in TRAPS

Excerpt

Mutations in TNFR1 cause the familial autosomal-dominant autoinflammatory disorder TNF receptor-associated periodic syndrome (TRAPS). Most TRAPS-associated mutations in TNFR1 disrupt normal receptor function and cause retention of the mutant protein in the ER. Cells expressing mutant TNFR1 have enhanced MAP Kinase activation at baseline and hyper-responsiveness to innate immune stimuli, which is aided by the wild-type receptor. We have previously found that reactive oxygen species (ROS) generated by mitochondrial respiration is critical for this phenotype [1]. TRAPS patient cells, and cells from TNFR1 mutant mice display enhanced basal and maximal oxygen consumption, suggesting that enhanced mitochondrial respiration can in some circumstances contribute to acute inflammatory responses through increased generation of ROS. …