The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice

Simone Patergnani, Méghane S. Bataillard, Alberto Danese, Stacy Alves, Chantal Cazevieille, René Valéro, Lisbeth Tranebjærg, Tangui Maurice, Paolo Pinton, Benjamin Delprat*, Elodie M. Richard

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

4 Citationer (Scopus)

Abstract

Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM’s integrity and functionality. It may open new treatment perspectives for patients with WLS.
OriginalsprogEngelsk
TidsskriftAutophagy
Vol/bind20
Udgave nummer9
Sider (fra-til)2055-2066
Antal sider12
ISSN1554-8627
DOI
StatusUdgivet - 2024

Bibliografisk note

Publisher Copyright:
© 2024 Informa UK Limited, trading as Taylor & Francis Group.

Citationsformater