Figure 7 .

Summary of metabolic responses to the energetic challenge in patient fibroblasts. Mitochondrial metabolism and energy production plays a key role in cellular homeostasis. The CHCHD10 p.R15L variant leads to a complex I deficiency, resulting in an increase in the NADH/NAD⁺ ratio and a downregulation of the TCA cycle. Under nutrient stress, the energy deficit in leads to an increase in the AMP/ATP ratio, increased phosphorylation of AMPK and the subsequent activation of catabolic pathways and the downregulation of the growth targeted mTOR pathway. This metabolic stress results in the activation of the UPR of the ER through IRE1/XBP1. The upregulation of different proteases and heat shock proteins, and the metabolic cytokines FGF21 and GDF15, demonstrates the simultaneous activation of the mtUPR. Finally, patient cells show increased cell death through apoptotic processes independent of JNK. This scheme was created with BioRender.