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.
摘要：
WFS1（WolframinER跨膜糖蛋白）中的显性变体，编码线粒体相关内质网（ER）膜（MAM）驻留蛋白的基因，与Wolfram样综合征（WLS）有关。在体外和体内，WFS1损失导致ER向线粒体钙（Ca2+）转移减少，线粒体功能障碍，并增强巨自噬/自噬和线粒体自噬。然而,在WLS的病理背景下，突变蛋白是否触发相同的细胞过程是未知的。这里,我们表明，在人成纤维细胞和鼠神经元培养中，WLS蛋白WFS1E864K导致线粒体生物能学和Ca2摄取减少，线粒体质量系统机制的放松调节，和自噬通量的改变。此外，在Wfs1E864K鼠标中，这些改变伴随着MAM数量的减少。这些发现揭示了WS和WLS之间的病理生理相似性，强调WFS1对于MAM的完整性和功能的重要性。它可能为WLS患者开辟新的治疗前景。缩写：BafA1：bafilomycinA1；ER：内质网；HSPA9/GRP75：热休克蛋白家族A（Hsp70）成员9；ITPR/IP3R：肌醇1,4,5-三磷酸受体；MAM：线粒体相关的内质网膜；MCU：线粒体钙单质转运蛋白；MFN2：抗线粒体1型ACfAA：VfAA依赖性阴离子1；V
