Mitochondrial Remodeling and Impaired Bioenergetics Define Neuronal Vulnerability in Fragile X-Related Disorders

Abstract

Fragile X syndrome (FXS) and related conditions associated with FMR1 gene alterations have increasingly been linked to mitochondrial dysfunction, although most available evidence derives from peripheral cell models. Whether these abnormalities also occur in disease-relevant neuronal populations remains largely unknown. Building on our previous observations in patient-derived fibroblasts, we investigated mitochondrial structure and function in neurons differentiated from induced pluripotent stem cells (iPSCs) generated from individuals with FXS and carriers of unmethylated full mutations, using matched healthy control lines. Mitochondrial integrity, bioenergetic properties, and network organization were evaluated to determine whether FMR1-associated mitochondrial defects are preserved in a neuronal context. Mitochondrial abnormalities previously identified in fibroblasts were recapitulated in iPSC-derived neurons. These findings demonstrate that impaired mitochondrial dynamics and function are conserved across different cell types, indicating that mitochondrial dysfunction represents a relevant cellular feature of FXS and related FMR1-associated conditions. Our results indicate that mitochondrial dysfunction is a shared feature of FMR1-related neuronal models, while the underlying patterns of mitochondrial remodeling are influenced by the specific FMR1-associated condition. These results support a role for mitochondrial alterations in FMR1-related neuronal dysfunction and provide a basis for the further investigation of the mechanisms linking mitochondrial homeostasis to the pathophysiology of FXS and related conditions.