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Roles of mitochondria in healthy and diseased myelin

Final Report Summary - MITOMYELIN (Roles of mitochondria in healthy and diseased myelin)

The myelin sheath that covers the large axons of our peripheral nervous system is essential for an efficient nerve conduction despite the long distances that are covered. As the myelinating Schwann cells of the peripheral nervous system are the main cells that interact with the axon along its journey to its target, an intimate relationship is established very early between axons and glial cells. This includes an essential metabolic crosstalk, which remains partly understood. In particular, the functions of mitochondria, which play a central role in the cell metabolism, in this crosstalk remained unclear. The goal of this ERC project was to investigate the roles of mitochondria in the maintenance of the myelinated fibre in the peripheral nervous system. As mitochondria physiology change very quickly after the death of the organism, we chose to investigate this physiology in living anesthetized mice using live imaging of fluorescent probes targeted to mitochondria. We found that mitochondria play a central role in the degeneration process of the myelin, a phenomenon involved in numerous peripheral nerve diseases. The discovery of a critical step in the myelin degeneration will allow us to design preventive and curative treatment for demyelinating peripheral neuropathies. In addition, we found that myelinating Schwann cells use Warburg effect, a cancer-like metabolism, to supply energy to peripheral nerve axons. Blocking this mechanism results in a long-term degradation of the peripheral nervous system suggesting this may be one of the causes of several peripheral neuropathies. Finally, we were able to observe mitochondrial production of ATP and ROS in real-time in vivo in quiescent and active axons and in myelinated or demyelinated axons. Our data show that demyelination or mitofusin 2 mutations, the cause of CMT2A disease, disrupt the coupling between the production of ATP and the genesis of ROS resulting in more ROS generated in absence of ATP production. This may represent a significant cause for the alteration of the axonal function and maintenance in several diseases.