Both histological and imaging analyses implicate metabolic stress as a contributor to lesion evolution in MS57–64, with reduced focal cerebral blood flow associated with chronic hypoxia, lesion formation and axonal degeneration, and evidence of axonal metabolic dysfunction. Autophagy is a process of degradation of cellular components by the lysosomal pathway as an adaptive response to stress, to mediate cytoprotective responses and enhance energy production. Blocking autophagy of metabolically stressed OLs in vitro by using chloroquine results in increased cell death65. This could potentially reflect reduced energy production and/or failure of the auto-phagosomal/lysosomal pathway to clear tissue injury-mediating products. Excess autophagy activation itself can contribute to cell death mediated via Na+/K+-ATPase, resulting in cell swelling and plasma membrane rupture (a process known as autosis)66 and by activating other selected cell death pathways, such as apoptosis67 and necroptosis68. Metabolic stress can also trigger mitochondrial permeability transition-driven necrosis which involves the opening of a supramolecular complex (‘permeability transition pore complex’) at the junctions between inner and outer mitochondrial membranes; OLs in MS lesions express cyclophilin D (CYPD), a driver of mitochondrial pore-driven necrosis; deletion protects against neurodegeneration in demyelinating experimental models of MS69.
