PR002082 (Project)

Description:Adenylosuccinate lyase (ADSL) deficiency (ADSLd) is a rare autosomal recessive defect of purine metabolism associated with a wide range of clinical manifestations. Despite ADSL implication in purine synthesis, no additional molecular alterations have been identified as a cause of ADSLd besides the accumulation of toxic substrates. Here we uncover a novel association between ADSLd and mitochondrial dysfunction, which is characterized by an increase in fragmentation and reduction in respiration and ATP production. The extent of this mitochondrial dysfunction is directly proportional to the pathological manifestations of ADSLd, which are predominantly observed in tissues that rely heavily on mitochondria. Our analysis also unveils a striking defect in mitochondrial dynamics and transport, which are associated with the suppression of ERK2 and AKT function. Remarkably, the mitochondrial phenotype can be rescued in part by overexpression of a constitutive form of ERK2 or through the administration of purine intermediates. This scenario provides an alternative explanation of ADSLd onset, reorienting research towards developing innovative therapeutic strategies based on the restoration of mitochondrial metabolism.