P08 - Structural and functional changes of the axonal mitochondrial inner membrane in vivo in a dysmyelinating mouse model

Myelinated axons in the central nervous system exist in a close metabolic relationship with the myelinating oligodendrocyte. This axo-glia unit is adapted to the high energy demands of saltatory action potential propagation which critically depends on the function of axonal mitochondria. Neurodegeneration accompanied by axonal swellings and alterations in morphology and function of axonal mitochondria is a hallmark of dys- and demyelinating disease states. Here we want to study the molecular and functional changes of the inner mitochondrial membrane of axonal mitochondria in a well-established dysmyelinating mouse model, the PLPnull mouse. We aim at investigating these adaptive changes in vivo using the optic nerve which is composed of the axons of the retinal ganglion cells. We will apply 3D electron microscopy using focused-ion beam scanning electron microscopy and electron tomography to investigate mitochondrial distribution, shape and cristae structure. By using STED microscopy and immunoelectron microscopy we will investigate compositional changes of the inner membrane. Assays addressing the activity of complex II and IV, live imaging of mitochondrial transport, ATP levels and the application of a potentiometric dye will provide indications for changes in functionality. In this project we will combine our experience in mouse models, electron microscopic volume imaging and optic nerve live imaging with the expertise provided by the consortium.