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 2

VDAC1 controls mitochondrial calcium release during demyelination.

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VDAC1 controls mitochondrial calcium release during demyelination. (A) V...
(A) VDAC1 shRNA validation in vitro. Mouse MSC80 cells were transfected with plasmids expressing VDAC1 shRNAs, and VDAC1 protein amounts were quantified by Western blot. GAPDH was used as loading control. n = 4 independent experiments. (B) AAV-expressing VDAC1 shRNA 2 or 3 or control shRNA together with GFP (green, white arrows) was injected in mouse sciatic nerve (left). Cells expressing VDAC1 shRNAs express less VDAC1 (blue) in their mitochondria (red) than noninfected surrounding cells or cells expressing control shRNA. Scale bar: 10 μm. Quantification of VDAC1 fluorescence intensity in infected cells (right). (C) Mitochondrial calcium, (D) cytoplasmic calcium, (E) mitochondrial pH, or (F) mitochondrial motility changes in mSCs expressing control shRNA in control conditions (gray) or after crush (black) or expressing VDAC1 shRNAs 2 (blue) or 3 (red) after crush or treatment with TRO19622 (TRO) before crush (green). Asterisks mark statistical differences compared with noncrushed nerve. Quantification of (G) mitochondrial calcium, (H) cytoplasmic calcium, (I) mitochondrial pH, or (J) mitochondrial motility in mSCs 2 hours after vehicle or MJ treatment (3 mmol). (K) Mitochondrial calcium changes in mice treated with vehicle or 500 μM CsA 30 minutes before crush or in control conditions (noncrushed mice). (L) Mitochondrial calcium and (M) cytoplasmic calcium changes of WT and CypD–/– mice after crush or control conditions. Data are expressed as the mean ± SEM. n = 3–8 mice for each group. Asterisks mark statistical differences over control conditions (noncrushed nerve). *P < 0.05, **P < 0.01, 2-tailed Student’s t test, compared with noncrushed nerves.