In vivo analysis of mitochondrial dynamics, structure and function in animal models of multiple sclerosis

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Multiple sclerosis (MS) is a common neuroinflammatory disease that causes severe disability due to progressive neuronal damage. Recent work has identified mitochondria as key players in neuronal damage in MS, suggesting that this disease could be considered an acquired mitochondriopathy. Histopathological studies indicate that mitochondria pile up in MS lesions, where they appear morphologically altered and functionally impaired. Using an in vivo microscopy approach we could show that the accumulation of such damaged mitochondria precedes axon loss in an animal model of MS, experimental autoimmune encephalomyelitis (EAE) and that locally inhibiting mitochondrial function can recapitulate key aspects of immune-mediated axon damage. In addition to local axonal injury inside inflammatory lesions, MS and EAE also show progressive dysfunction and loss of synapses at remote sites, suggesting that a distal axon dystrophy might further exacerbate the disease. Supporting this notion, we have recently demonstrated that axons, which pass inflammatory lesions, lack mitochondrial transport. This results in a chronic undersupply of organelles in axon terminals distal of inflamed areas. Together, these findings suggest that altered mitochondrial dynamics could contribute in two ways to neuronal damage in MS: On the one hand, accumulation of dysfunctional mitochondria could injure axons inside inflammatory lesions, while on the other hand a dearth of mitochondria could contribute to distal neurite dystrophy. The mechanisms that cause these distinct mitochondrial pathologies and their relationship to structural damage of axons and synapses, however, remain largely unresolved. To address this, we have over the recent years developed a range of in vivo imaging tools to follow the dynamics, structure and function of mitochondria with single organelle resolution in the spinal cord of living mice. We will now combine these tools with correlated electron microscopy and genetic and pharmacological manipulations to analyse the role of disrupted mitochondrial dynamics and function in acute and chronic MS models and test the following hypotheses: Hypothesis 1| Altered fusion and fission, together with disrupted axonal transport, explain the accumulation of mitochondria in neuroinflammatory lesions. Hypothesis 2| The accumulation of mitochondria in inflammatory lesions results in mitochondrial dysfunction, specifically in alterations of mitochondrial calcium handling and electron transport chain function, which promote focal axonal degeneration in acute neuroinflammatory lesions. Hypothesis 3| The diminished supply of intact mitochondria alters the mitochondrial pool in distal axon arbors and thereby causes progressive axonal and synaptic dystrophy in chronic neuroinflammatory lesions.