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

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.Abbreviations BafA1 bafilomycin A1; ER endoplasmic reticulum; HSPA9/GRP75 heat shock protein family A (Hsp70) member 9; ITPR/IP3R inositol 1,4,5-trisphosphate receptor; MAM mitochondria-associated endoplasmic reticulum membrane; MCU mitochondrial calcium uniporter; MFN2 mitofusin 2; OCR oxygen consumption rate; ROS reactive oxygen species; ROT/AA rotenone+antimycin A; VDAC1 voltage dependent anion channel 1; WLS Wolfram-like syndrome; WS Wolfram syndrome; WT wild-type.