Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis

• DOI: 10.1038/srep33249
• Publication Date: 2016-09-14T07:31:25Z
• Authors: Mona Sadeghian; Vincenzo Mastrolia; Ali Rezaei Haddad; Angelina Mosley; Gizem Mullali; Dimitra Schiza; Marija Sajic; Iain Hargreaves; Simon Heales; Michael R. Duchen; Kenneth J. Smith
• Keywords: Inflammation; RM; 0303 health sciences; Electron Transport Complex I; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Phosphofructokinase-2; Article; Axons; Mitochondria; Disease Models, Animal; Mice; 03 medical and health sciences; Spinal Cord; Diseases of the nervous system; Animals; Humans; Nervous System Diseases; Neuroscience

AbstractNeuroinflammation can cause major neurological dysfunction, without demyelination, in both multiple sclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.