The Wolfram-like variant WFS1^E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice

Abstract

Dominant variants inWFS1, a gene coding for the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein Wolframin, have been associated with Wolfram-like syndrome (WLS).In vitroandin vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced autophagy and mitophagy. However, in 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, WLS protein WFS1E864Kleads to decreases in mitochondria bioenergetics and Ca2+uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in theWfs1E864Kmouse, 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, until now non-existent, for patients with WLS.