Review: Mitochondria and disease progression in multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Recent evidence suggests that dysfunction of surviving demyelinated axons and axonal degeneration contribute to the progression of MS. We review the evidence for and potential mechanisms of degeneration as well as dysfunction of chronically demyelinated axons in MS with particular reference to mitochondria, the main source of adenosine-5'-triphosphate in axons. Besides adenosine-5'-triphosphate production, mitochondria play an important role in calcium handling and produce reactive oxygen species. The mitochondrial changes in axons lacking healthy myelin sheaths as well as redistribution of sodium channels suggest that demyelinated axons would be more vulnerable to energy deficit than myelinated axons. A dysfunction of mitochondria in lesions as well as in the normal-appearing white and grey matter is increasingly recognized in MS and could be an important determinant of axonal dysfunction and degeneration. Mitochondria are a potential therapeutic target in MS.

Figure 1

Schematic diagram of the mitochondrial respiratory chain located in the inner mitochondrial membrane. The electrons (e⁻) donated to complex I and complex II flow through to complex IV where they are donated to oxygen to form water. The protons (H⁺) are pumped into the intermembrane space from mitochondrial matrix to generate mitochondrial membrane potential that drives ATP synthase to generate ATP. Cyanide is an inhibitor of complex IV. Nitric oxide (NO) competes with oxygen for the oxygen binding sites and may irreversibly inhibit complex IV. Complex I and complex III are recognized sites of reactive oxygen species (ROS) production.

Figure 2

Mitochondrial respiratory chain complex IV activity in dysmyelinated and unmyelinated axons. The Luxol Fast Blue staining is decreased in the spinal cord white matter of shiverer mice containing dysmyelinated axons (A) compared with controls (B). The histochemical analysis of complex IV activity in serial sections shows increased complex IV activity in the white matter including the dorsal columns in shiverer mice (C) compared with controls (D) [54]. In the lamina cribrosa where axons are unmyelinated (E), the complex IV activity (F) is notably increased compared with the myelinated segments identified by Luxol Fast Blue staining (E) [55].

Figure 3

The mitochondrial respiratory chain complex IV subunit-I (COX-I), a catalytic subunit of complex IV, immunoreactive elements (A, green) and mitochondrial mass, judged by porin (B, green) immunoreactive elements, in acute pattern III MS lesions. The COX-I reactive elements are sparse within axons (red) in pattern III MS lesions compared with mitochondrial elements, when identified using confocal microscopy. The insert shows a x–z section through an axon containing mitochondria [66]. In myelinated axons, COX-I immunoreactivity is comparable with porin (not shown). The axons are identified by neurofilament immunoreactivity (A and B, red).