Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders

Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unravelled Beclin‐1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell‐penetrating autophagy‐inducing Tat‐Beclin‐1 (TB‐1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB‐1 reduced urinary orotic acid and improved survival under protein‐rich diet in spf‐ash mice, a model of OTC deficiency (proximal UCD). In Asl Neo/Neo mice, a model of ASL deficiency (distal UCD), TB‐1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in Asl Neo/Neo mice. In conclusion, Beclin‐1‐dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification. TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder). TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder). ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle.