Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies
Sergio Gonzalez, … , Guy Lenaers, Nicolas Tricaud
Sergio Gonzalez, … , Guy Lenaers, Nicolas Tricaud
Published March 1, 2016; First published February 15, 2016
Citation Information: J Clin Invest. 2016;126(3):1023-1038. https://doi.org/10.1172/JCI84505.
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Research Article Cell biology Neuroscience

Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

Abstract

Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondrial calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondrial calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies.

Authors

Sergio Gonzalez, Jade Berthelot, Jennifer Jiner, Claire Perrin-Tricaud, Ruani Fernando, Roman Chrast, Guy Lenaers, Nicolas Tricaud

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Figure 1

Mitochondrial physiology changes during SC demyelination.

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Mitochondrial physiology changes during SC demyelination. (A) Schematic ...
(A) Schematic representation of the imaging technique (left). mSCs are labeled with E-cadherin (green), mitochondria are labeled with mito-dsRed2 (red), and the cell nucleus is labeled with DAPI (blue) (middle). Scale bar: 50 μm. Representative image of mitochondria imaged with a multiphoton microscope (right). Scale bar: 5 μm. SN, sciatic nerve. (B) Mitochondrial calcium amount (mito-GCaMP2), (C) cytoplasmic calcium amount (cyto-GCaMP2), (D) mitochondrial pH (mito-SypHer), and (E) mitochondrial motility (mito-dsRed2) in mSCs of control and crushed nerves. Probe intensities are represented as fold over basal conditions (before crush), and motility is represented as μm traveled in 1 minute over 300 minutes of time-lapse acquisition. Representative images of labeled mitochondria. Scale bar: 5 μm (B and D); 100 μm (C). (F) Ratio of mitochondrial fusion and fission events in control and crushed nerves. (G) Representative images of mSC mitochondria and mitochondrial length quantification in control and crushed nerves after 300 minutes of time-lapse imaging. Scale bar: 3 μm. (H) Frequency histogram of mitochondrial length in control and crush conditions. No significant difference was found. Data are expressed as the mean ± SEM. n = 3–6 mice for each group. Asterisks mark statistical differences compared with noncrushed nerves. *P < 0.05, **P < 0.01, 2-tailed Student’s t test.