Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is a rare inherited neuropathy linked to mutations in the MTMR5/SBF1 gene. This gene encodes a pseudophosphatase that helps regulate phosphoinositide metabolism and autophagy, the cellular recycling pathway essential for maintaining protein and organelle quality. While most studies focus on neuronal cells, researchers recently investigated how MTMR5/SBF1 mutations affect non-neuronal cells, particularly patient-derived skin fibroblasts.
Autophagy usually helps clear misfolded proteins and damaged mitochondria through lysosomal degradation. Neurons depend heavily on this process to maintain their long-term survival. In CMT4B3 fibroblasts, researchers found that basal autophagy remained intact, but the cells could not efficiently increase autophagic flux when stressed by mitochondrial damage or protein misfolding. This suggests that global autophagy regulation is impaired under challenging conditions.
Interestingly, mitophagy—the selective removal of damaged mitochondria—was strongly activated in mutant fibroblasts. This process occurred through the PINK1–PRKN pathway, a well-known mechanism for mitochondrial quality control. Despite efficient clearance of defective mitochondria, these cells accumulated large amounts of protein aggregates. This finding highlights an imbalance: while mitochondria are removed effectively, misfolded proteins are not adequately degraded.
The results point to a selective shift in autophagy regulation caused by MTMR5/SBF1 deficiency. Instead of coordinating both mitophagy and macroautophagy, patient cells appear to prioritize mitochondrial clearance while failing to resolve proteotoxic stress. This imbalance may contribute to disease mechanisms in CMT4B3, where neurons, with their high reliance on proteostasis, could be especially vulnerable.
Overall, the study reveals that MTMR5/SBF1 mutations uncouple mitophagy from macroautophagy. Protein aggregate buildup alongside enhanced mitochondrial turnover reflects a unique autophagic phenotype. These insights not only shed light on CMT4B3 pathology but also emphasize the importance of selective autophagy regulation in inherited neuropathies. Future research in neuronal models and animal systems may help identify therapeutic strategies aimed at restoring balanced autophagy and improving protein quality control in affected patients.