Patient-derived cells reveal metabolic and lysosomal defects in TFE3 neurodevelopmental disorder

Patient-derived fibroblasts carrying mutations associated with TFE3-associated neurodevelopmental disorder show altered energy metabolism, dysfunctional lysosomes and a destabilized interface with the extracellular matrix, according to a study published in Nature Communications. The research used cells from patients with TFE3-NDD, a recently described disorder caused by mutations that disrupt the interface between the transcription factor TFE3 and Rag GTPases. These mutations lead to constitutive nuclear localization of TFE3, leaving this stress-response factor persistently activated.

The strongest metabolic change was a pronounced shift toward oxidative phosphorylation, or OXPHOS. The mutant cells became more committed to this metabolic state, which the researchers describe as “metabolic rigidity.” This commitment was accompanied by increased vulnerability to energy failure, showing that the altered metabolic profile did not translate into greater resilience. The findings suggest that chronic TFE3 activation compromises cellular adaptability rather than simply enhancing cellular activity.

The lysosomal changes were similarly contradictory. Although mutant cells developed a massive expansion of their lysosomal compartment, the organelles showed a qualitative decline in function. TFE3-NDD fibroblasts exhibited impaired lysosomal acidification, defective protease maturation, increased lysosomal exocytosis and aberrant secretion of cathepsin K. The abundance of lysosomal structures therefore did not correspond to normal lysosomal performance. Together, the observations indicate that chronic activation of TFE3 is associated with defects across several aspects of cellular homeostasis.

The abnormal secretory phenotype was coupled with changes in cell migration and cell–matrix interactions. Fibroblasts carrying TFE3-NDD mutations migrated less effectively, while the coordination between actomyosin tension and focal adhesion maturation was defective. The researchers also observed a loss of synaptic stabilizers, proteins associated with maintaining synaptic architecture. These findings provide a possible cellular link between persistent TFE3 activation and the tissue malformations and neurodevelopmental deficits that define the disorder, but the experiments were conducted in patient-derived fibroblasts and do not establish how the same processes contribute to symptoms in the nervous system.

TFE3-NDD cells also shared a molecular signature with TFE3-dependent cancers, including translocation renal cell carcinoma: high OXPHOS and ferroptosis resistance. The comparison establishes a resemblance between these distinct disease contexts, but it does not make TFE3-NDD a cancer or show that both conditions respond alike to treatment. More broadly, the study portrays chronic TFE3 hyperactivation as a failure of cellular homeostasis, linking metabolic rigidity and lysosomal abnormalities with secretory changes and extracellular-matrix instability. Its scope remains limited to the studied cellular model, leaving the relevance of these mechanisms across human tissues and their connection to the disorder’s clinical features to be determined by further research.

Subject of Research: Cellular mechanisms of chronic TFE3 activation in TFE3-associated neurodevelopmental disorder

Article Title: Chronic TFE3 activation in TFE3-associated neurodevelopmental disorder drives metabolic rigidity, lysosomal failure, and cell-extracellular matrix destabilization

Article References: Martina, J. A., Prashar, A., Pasapera, A. M., Rollins, K., Jeong, E., & Puertollano, R. (2026). Chronic TFE3 activation in TFE3-associated neurodevelopmental disorder drives metabolic rigidity, lysosomal failure, and cell-extracellular matrix destabilization. Nature Communications. https://doi.org/10.1038/s41467-026-78845-7

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78845-7

Keywords: TFE3, neurodevelopmental disorder, patient-derived fibroblasts, oxidative phosphorylation, metabolic rigidity, lysosomal dysfunction, extracellular matrix, cell migration, ferroptosis resistance, Chronic, activation, TFE3-associated