Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts.

Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is an ultra-rare autosomal recessive neuropathy caused by mutations in the MTMR5/SBF1 gene. In this study, we characterized dermal fibroblasts derived from a patient carrying compound-heterozygous MTMR5/SBF1 variants (R763H/G1064E) and identified alterations affecting mitochondrial metabolism and cellular stress pathways. Patient fibroblasts exhibited fragmented mitochondrial networks with a shift toward fission, together with reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved. In line with our previous evidence of enhanced mitophagy, these findings support the presence of altered mitochondrial quality control. The reduction in cellular energy production was not accompanied by increased glycolytic activity, indicating a metabolically quiescent phenotype. Transcriptomic profiling revealed dysregulation of the PI3K/AKT signalling pathway. AKT phosphorylation at Ser473 was increased in the absence of complete canonical AKT activation. These signalling changes were associated with increased expression of p53 and p21 and with features consistent with premature cellular senescence. Overall, our findings identify metabolic quiescence and premature senescence as previously unrecognized aspects of CMT4B3 cellular pathology and suggest that altered coordination between mitochondrial metabolism and intracellular signalling may contribute to disease pathogenesis.