Mitochondrial changes within axons in multiple sclerosis

Abstract

Multiple sclerosis is the most common cause of non-traumatic neurological impairment in young adults. An energy deficient state has been implicated in the degeneration of axons, the pathological correlate of disease progression, in multiple sclerosis. Mitochondria are the most efficient producers of energy and play an important role in calcium homeostasis. We analysed the density and function of mitochondria using immunohistochemistry and histochemistry, respectively, in chronic active and inactive lesions in progressive multiple sclerosis. As shown before in acute pattern III and Balo's lesions, the mitochondrial respiratory chain complex IV activity is reduced despite the presence of mitochondria in demyelinated axons with amyloid precursor protein accumulation, which are predominantly located at the active edge of chronic active lesions. Furthermore, the strong non-phosphorylated neurofilament (SMI32) reactivity was associated with a significant reduction in complex IV activity and mitochondria within demyelinated axons. The complex IV defect associated with axonal injury may be mediated by soluble products of innate immunity, as suggested by an inverse correlation between complex IV activity and macrophage/microglial density in chronic lesions. However, in inactive areas of chronic multiple sclerosis lesions the mitochondrial respiratory chain complex IV activity and mitochondrial mass, judged by porin immunoreactivity, are increased within approximately half of large (>2.5 microm diameter) chronically demyelinated axons compared with large myelinated axons in the brain and spinal cord. The axon-specific mitochondrial docking protein (syntaphilin) and phosphorylated neurofilament-H were increased in chronic lesions. The lack of complex IV activity in a proportion of Na(+)/K(+) ATPase alpha-1 positive demyelinated axons supports axonal dysfunction as a contributor to neurological impairment and disease progression. Furthermore, in vitro studies show that inhibition of complex IV augments glutamate-mediated axonal injury (amyloid precursor protein and SMI32 reactivity). Our findings have important implications for both axonal degeneration and dysfunction during the progressive stage of multiple sclerosis.

White-Matter Astrocytes, Axonal Energy Metabolism, and Axonal Degeneration in Multiple Sclerosis

“…These spontaneous improvements may reflect either restored mitochondrial activity or a compensatory increase in the number of mitochondria. Histopathological studies found increased numbers of mitochondria and an upregulation of mitochondrial cytochrome C oxidase (complex IV) in axons in both chronic lesions and normal appearing white matter of MS subjects (Mahad et al, 2009;Witte et al, 2009). …”

Glutathione in multiple sclerosis: More than just an antioxidant?

“…10 Dysfunctional mitochondria were recently shown to be implicated in both early and chronic stages of MS pathology, actively contributing to both axonal and neuronal injury. [11][12][13] The cause of mitochondrial dysfunction in patients with MS has been debated, but evidence is emerging that ROS production by macrophages/microglia might induce mitochondrial dysfunction in patients with MS, 10,13 possibly via oxidative damage to mitochondrial DNA. 12 Oxidative damage contribution to MS lesion formation In the initial phase of MS lesion formation, locally produced ROS can induce blood-brain barrier (BBB) disruption and promote leukocyte migration.…”

“…[11][12][13] The cause of mitochondrial dysfunction in patients with MS has been debated, but evidence is emerging that ROS production by macrophages/microglia might induce mitochondrial dysfunction in patients with MS, 10,13 possibly via oxidative damage to mitochondrial DNA. 12 Oxidative damage contribution to MS lesion formation In the initial phase of MS lesion formation, locally produced ROS can induce blood-brain barrier (BBB) disruption and promote leukocyte migration. In vitro studies demonstrate that ROS promote BBB permeability, by causing cytoskeletal rearrangements in endothelial cells, and redistribution and loss of tight junctions.…”

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

“…Although most demyelinated axons compensate for loss of oligodendrocytes/myelin, additional insults to axonal mitochondria impair axonal metabolism, increase axonal Ca 2+ , and promote progressive disruption of mitochondrial function (11,12). Changes in axonal mitochondria have been described in chronically demyelinated axons in postmortem multiple sclerosis tissue, and include decreased expression of nuclear-encoded mitochondrial genes (13), reduced mitochondrial respiration (14), and genetic alterations in mitochondrial DNA (15). A vicious cycle of reduced ATP production and increased axonal Ca 2+ results in degeneration of the chronically demyelinated axon.…”