In Wolfram syndrome (WFS), intracellular endoplasmic reticulum stress and reduced levels of the protein wolframin lead to diabetes and neurodegeneration. In addition, deficiency of the wolframin-encoding gene, WFS1, is known to disrupt calcium balance and change mitochondrial dynamics. Unfortunately, there is no effective treatment for WFS, but better characterization of its mechanisms might aid in therapy development. To further investigate WFS, a recent study analyzed the mRNA transcript and protein profiles in a human cell WFS model. The levels of proteins in various signaling pathways differed between the WFS cells and normal control cells. For example, proteins involved in oxidative phosphorylation, the major energy-producing pathway in mitochondria, were downregulated in the WFS cells. while proteins in other energy generation pathways were upregulated. Analysis of publicly available sequencing data confirmed that in mouse hippocampal tissues, WFS1 deficiency is associated with downregulation of oxidative phosphorylation proteins and molecules that help import proteins into the mitochondria. Although additional experiments with other cell types are needed, the results provide more information on the mechanisms of WFS, which may help researchers design new therapies for this rare but serious condition.