Increased astrocytic expression of mitochondrial antioxidant enzymes in active multiple sclerosis lesions

Axonal degeneration is widespread in multiple sclerosis (MS) lesions and is considered to be the main pathological correlate of permanent disability in patients. Recent, evidence suggests that reactive oxygen species (ROS) derived from inflammatory cells drive axonal degeneration in active MS lesions by inducing intra-axonal mitochondrial dysfunction. Besides being a target of exogenous ROS, mitochondria are also capable of producing vast amounts of ROS themselves. To protect mitochondria from ROS-induced damage, an intricate system of mitochondrial-specific antioxidant enzymes exists that detoxifies the various ROS. Peroxiredoxin-3 (Prx3) and thioredoxin-2 (Trx2) are two key antioxidant enzymes which work in concert to detoxify peroxides in mitochondria. In this study, we analyzed expression of Prx3 and Trx2 in various MS white matter lesions and observed a striking upregulation of these mitochondrial antioxidants in reactive astrocytes in inflammatory MS lesions. To assess the functional role of this upregulation, we overexpressed Prx3 and Trx2 in an astrocytoma cell line. Astrocytoma cells overexpressing mitochondrial antioxidant enzymes were less susceptible to ROS-induced cell death compared to control cells. Moreover, we observed that neuroblastoma cells cocultured with either Prx3 or Trx2 overexpressing astrocytoma cells were less vulnerable to exogenous ROS compared to neuroblastoma cells co-cultured with control astrocytoma cells. Taken together, we here provide strong evidence of increased expression of Prx3 and Trx2 in reactive astrocytes in inflammatory MS lesions. We speculate that upregulation of mitochondrial antioxidants preserves mitochondrial function and protects astrocytes from oxidative stress and subsequent cell death, and might even contribute to axonal survival.