Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis.
The mechanisms of axonal and neuronal degeneration causing visual and neurologic disability in multiple sclerosis are poorly understood. Here we explored the contribution of mitochondria to neurodegeneration in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis. Oxidative injury to the murine mitochondrion preceded the infiltration of inflammatory cells, classically heralded as the mediators of demyelination and axonal injury by transection. Nitration of mitochondrial proteins affected key subunits of complexes I and IV of the respiratory chain and a chaperone critical to the stabilization and translocation of proteins into the organelle. Oxidative products were associated with loss of mitochondrial membrane potential and apoptotic cell death. Reductions in the rate of synthesis of adenosine triphosphate were severe and even greater than those associated with disorders caused by mutated mitochondrial DNA. Mitochondrial vacuolization, swelling, and dissolution of cristae occurred in axons as early as 3 days after sensitization for experimental autoimmune encephalomyelitis. Our findings implicate mitochondrial dysfunction induced by protein inactivation and mediated by oxidative stress initiates a cascade of molecular events leading to apoptosis and neurodegeneration in experimental autoimmune encephalomyelitis that is not mediated by inflammatory cells.
Qi
Xiaoping
X
Department of Ophthalmology, the University of Florida College of Medicine, Gainesville, Florida 32610-0284, USA.
Lewin
Alfred S
AS
Sun
Liang
L
Hauswirth
William W
WW
Guy
John
J
D000595:Amino Acid Sequence; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry*; D017382:Reactive Oxygen Species
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D019001:Nitric Oxide Synthase; D009584:Nitrogen