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 5

VDAC1 silencing and inhibition prevent SC mitochondrial anomalies and improve the phenotype of diabetic mice.

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VDAC1 silencing and inhibition prevent SC mitochondrial anomalies and im...
(A) Mitochondrial calcium, (B) cytoplasmic calcium, (C) mitochondrial pH, and (D) motility in mSCs of diabetic mice (db/db) in basal conditions are partially corrected during VDAC1 silencing or blocking. Immunohistochemistry for phospho–c-JUN in mSCs of control and diabetic mice after (E) VDAC1 silencing or (F) TRO19622 treatment. Arrows indicate infected mSC nuclei. Scale bar: 50 μm. Quantification of nuclear phospho–c-JUN represented as fold over control mice (db/+). Noninfected neighbor cells were used as internal controls. (G) Representative transmission electron micrograph images of sciatic nerve cross sections of control (db/+) and diabetic (db/db) mice after vehicle or TRO19622 treatment. Scale bar: 5 μm. (H) Scatterplot showing the g-ratio plotted against the axon diameter of control and diabetic mice treated with vehicle or TRO16922 for 30 days. (I) Average myelin g-ratio, axonal diameter, and number of myelinated axons in sciatic nerves of control and diabetic mice described in H. A minimum of 200 fibers was measured per animal. *P < 0.05, #P < 0.05, **P < 0.01, ##P < 0.01, 1-way ANOVA followed by a Dunnett’s multiple comparison post-hoc test.