Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis.
Neuroinflammation 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.
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Mona
M
Sadeghian
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Vincenzo
V
Mastrolia
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Ali
A
Rezaei Haddad
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Angelina
A
Mosley
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Gizem
G
Mullali
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Dimitra
D
Schiza
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Marija
M
Sajic
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
Iain
I
Hargreaves
Chemical Pathology, Great Ormond Street Children's Hospital, London, UK.
Simon
S
Heales
Cell and Developmental Biology, University College London, Gower Street, WC1E 6BT, London, UK.
Michael R
MR
Duchen
Department of Neuroinflammation, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, WC 1N 1PJ, London, UK.
Kenneth J
KJ
Smith
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D009103:Multiple Sclerosis; D009422:Nervous System Diseases / Q000201:enzymology* / Q000473:pathology; D025481:Phosphofructokinase-2 / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
D025481:Phosphofructokinase-2; D042967:Electron Transport Complex I