The release and uptake of calcium ions in the ER also influence cellular apoptosis. Researchers have discovered that wolframin functions as a calmomodulin (CaM) that interacts with many cellular proteins and controls the Ca2+ signaling pathways linked to apoptosis [
41]. Because increased ER stress levels lead to alterations in mitochondrial function, many researchers have suggested that WS1 may be defined as a mitochondrial disease [
47]. Numerous studies have provided evidence for a correlation between ER stress, high cytosolic Ca2+ levels, impaired mitochondrial dynamics, and inhibited neuronal development in WFS1-deficient neurons [
47,
48]. In healthy cells, WFS1 links to neuronal calcium sensor 1 (NCS1) and the inositol 1,4,5-trisphosphate receptor (IP3R) to promote the transfer of Ca2+ between the ER and the mitochondria. WFS1-deficient cells exhibit a significant reduction in NCS1 levels. Consequently, there is a loss of interactions between the ER and mitochondria, as well as a decrease in the transfer of calcium ions (Ca2+) [
47]. Therefore, there is a strong link between ER stress, modifications in cytosolic calcium levels, changes in mitochondrial dynamics, and developmental delay in WFS1-deficient neuronal cells [
49]. The modifications of mitochondria-associated ER membranes (MAMs) substantially influence this intricate pathogenic mechanism [
50]. MAMs, which are dynamic domains of interaction between mitochondria and ER, are the specific sites of several proteins that are implicated in UPR. These proteins are responsible for stabilizing the structure of MAMs and enabling the functional interaction between the ER and mitochondria. MAMs are responsible for the main transport of Ca2+ between the ER and mitochondria through the inositol 1,4,5-triphosphate receptor (IP3R) calcium channel [
50,
51]. The ER stress cascade inhibits the function of the IP3R calcium channel, leading to a subsequent disruption in the homeostasis of cytosolic Ca2+ levels. This altered pathway leads to alterations in mitochondrial dynamics, including inhibited mitochondrial fusions, abnormal mitochondrial trafficking, and enhanced mitophagy. Alterations in mitochondria lead to decreased ATP levels, which in turn affect the development of neurons. The analysis of the proteins involved in mitochondrial function revealed a down-regulation of the subunits of the respiratory chain complexes, an upregulation of the proteins involved in the Krebs cycle, and glycolysis mechanisms in WS neural stem cells (NSC) [
51]. There are similarities between the neurological and psychiatric symptoms of WS1 and those seen in mitochondrial diseases, which lead some authors to hypothesize that mitochondria may help explain the symptoms of WS1 [
52]. ER stress can cause serious changes in mitochondrial dynamics that can lead to a “mitochondrial phenotype” in WS1 patients [
47]. Zmyslowska et al. used human WS1 cells as a model to study the role of mitochondria in WS1. Initially, the researchers transformed skin fibroblasts into induced pluripotent stem cells (iPS), which subsequently underwent further differentiation into neural cells (NSC). They were then exposed to ER stress. In WS1 NSC cells, an evaluation of the proteins associated with mitochondrial activity revealed a down-regulation of the subunits of the respiratory chain complexes, an up-regulation of the proteins involved in the Krebs cycle, and mechanisms of glycolysis. In contrast, the control cells did not exhibit similar changes. Furthermore, it was suggested that alterations in the structure and function of the mitochondria are crucial in the development of WS1 [
51]. Wolframin directly influences the relationship between mitochondria and the ER, which is crucial for cellular metabolism and survival. The significant influence on cellular physiology explains the intricate nature of WS1, a disease that impacts several systems. Nevertheless, it is crucial to point out that WFS1 mutations do not directly affect the morphology and functions of the mitochondria [
53]. The influence of WFS1 on the mitochondria is mediated by the interactions between IP3R, voltage-dependent anion channel 1 (VDAC1), and glucose-regulated protein 75 (GRP75), also named heat shock protein family (Hsp70) member 9 (HSPA9). Thus, wolframin has a strong influence on both vesicular traffic and the ER-mitochondrial relationship. The connection between WFS1 and NCS1 is very important for this complicated link because it may explain the alterations found in the respiratory chain in WS1 patients and mutant mouse muscles [
53]. Koks et al. have also shown that the silencing of the WFS1 gene in HEK cells alters TOMM20, a protein associated with the ER-mitochondria transport [
55]. Thus, the mutations in the WFS1 gene do not have a direct influence on mitochondria. The impact on mitochondrial function occurs via a complicated interactions between multiple protein complexes, and the communication between the ER and mitochondria is critical for the disease’s underlying mechanisms.