Dr Don Mahad is a senior clinical fellow and my basic science research focuses on the role of mitochondria in progressive MS. Our research contributed to the identification of mitochondrial changes within neurons in progressive MS post-mortem tissue. The molecular and biochemical findings in neuronal cell bodies indicate a decrease in capacity to produce ATP while the mitochondrial changes in demyelinated axons indicate an increase in demand for energy. These findings have now been reproduced by seven independent groups using a number of different techniques. All the molecular changes observed within the neuronal cell bodies (grey matter) in progressive MS converge on mitochondria. A recent detailed collaborative study of nine experimental disease models, from my group and unpublished, indicates limited reflection of the mitochondrial changes intrinsic to neurons in progressive MS. I will summary the observations made in post-mortem MS tissue as well as highlight the limitations of existing experimental disease models in capturing the neuronal mitochondrial changes. I will discuss potential ways to model the findings in MS and identify novel targets for progressive MS.