Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy

Nathalie Bernard-Marissal, Gerben van Hameren, Manisha Juneja, Christophe Pellegrino, Lauri Louhivuori, Luca Bartesaghi, Cylia Rochat, Omar El Mansour, Jean-Jacques Médard, Marie Croisier, Catherine Maclachlan, Olivier Poirot, Per Uhlén, Vincent Timmerman, Nicolas Tricaud, Bernard L. Schneider, and Roman Chrast
PNAS February 5, 2019 116 (6) 2328-2337; published ahead of print February 5, 2019 https://doi.org/10.1073/pnas.1810932116

  1. Edited by Stephen T. Warren, Emory University School of Medicine, Atlanta, GA, and approved December 14, 2018 (received for review June 26, 2018)

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Significance

Interactions between mitochondria and the endoplasmic reticulum (ER) at the level of mitochondria-associated membranes (MAM) constitute a key signaling hub, emerging as a shared target altered in multiple neurodegenerative diseases. We use both in vivo and in vitro models of Charcot–Marie–Tooth type 2A, an axonal form of neuropathy, to demonstrate that the presence of mutated Mitofusin 2 leads to altered MAM. In neurons, these modifications occur concomitantly with activation of ER stress response, dysregulated calcium handling, and alterations in mitochondrial morphology and transport, collectively contributing to axonopathy. Importantly, the reported results indicate that the pathological consequences of mutated Mitofusin 2 may be targeted with drugs reinforcing the ER–mitochondria cross-talk and/or reducing ER stress.

Abstract

Mutations in the MFN2 gene encoding Mitofusin 2 lead to the development of Charcot–Marie–Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2R94Q induces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic reticulum and mitochondria contacts in CMT2A patient-derived fibroblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with endoplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly, pharmacological treatments reinforcing endoplasmic reticulum–mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.

Footnotes

  • ↵1To whom correspondence may be addressed. Email: nathalie.bernard.1{at}univ-amu.fr, bernard.schneider{at}epfl.ch, or roman.chrast{at}ki.se.

  • ↵2B.L.S. and R.C. contributed equally to this work.

  • Author contributions: N.B.-M., O.P., P.U., V.T., N.T., B.L.S., and R.C. designed research; N.B.-M., G.v.H., M.J., C.P., L.L., L.B., C.R., O.E.M., J.-J.M., M.C., C.M., and O.P. performed research; N.B.-M., G.v.H., M.J., C.P., L.L., L.B., O.P., P.U., V.T., N.T., B.L.S., and R.C. analyzed data; and N.B.-M., B.L.S., and R.C. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1810932116/-/DCSupplemental.

Published under the PNAS license.

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Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy
Nathalie Bernard-Marissal, Gerben van Hameren, Manisha Juneja, Christophe Pellegrino, Lauri Louhivuori, Luca Bartesaghi, Cylia Rochat, Omar El Mansour, Jean-Jacques Médard, Marie Croisier, Catherine Maclachlan, Olivier Poirot, Per Uhlén, Vincent Timmerman, Nicolas Tricaud, Bernard L. Schneider, Roman Chrast
Proceedings of the National Academy of Sciences Feb 2019, 116 (6) 2328-2337; DOI: 10.1073/pnas.1810932116
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