Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis

Soluble products of activated immune cells include reactive oxygen species (ROS) and nitric oxide (NO) with a high potential to induce biochemical mod ifications and degenerative changes in areas of inflammation in the central nervous system (CNS). Previously, we demonstrated an increased production of ROS by activated mononuclear cells (MNC) of patients with multiple scler osis (MS) compared to those of controls, and development of oxidative damag e to total DNA in association with inflammation in chronic active plaques. The current study aimed to determine whether mitochondrial (mt)DNA is affec ted by oxidative damage, and whether oxidative damage to mitochondrial macr omolecules (including mtDNA) is associated with a decline in the activity o f mitochondrial enzyme complexes. Using molecular and biochemical methods w e demonstrate a trend for impaired NADH dehydrogenase (DH) activity and a p ossible compensatory increase in complex IV activity in association with ox idative damage to mtDNA in chronic active plaques. Immunohistochemistry con firms the increase of oxidative damage to DNA predominantly located in the cytoplasmic compartment of cells in chronic active plaques. These observati ons suggest that oxidative damage to macromolecules develops in association with inflammation in the CNS, and may contribute to a decline of energy me tabolism in affected cells. As observed in neurodegenerative diseases of no n-inflammatory origin, decreased ATP synthesis can ultimately lead to cell death or degeneration. Therefore, elucidation of this pathway in MS deserve s further studies which may identify neuroprotective strategies to prevent tissue degeneration and the associated clinical disability. (C) 2000 Elsevi er Science B.V. All rights reserved.