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
Acknowledgements
We thank the patient and their family for their contribution to the study, Marc Thiry (University of Liege, Belgium) for his unvaluable advice for TEM analysis. We thank the breeding facility from the University of Montpellier (RAM-CECEMA) for their help in animal breeding and handling. We thank the Electronic Microscopy facilities of the Institut des Neurosciences de Montpellier for TEM acquisition. P.P. is grateful to C. degli Scrovegni for her continuous support.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data of this study is available from the corresponding authors upon reasonable request.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2341588
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.