New insights into the pathophysiology of methylmalonic acidemia

作者：PamelaSara E. Head, Jordan L. Meier, Charles P. Venditti · 发表于：Journal of Inherited Metabolic Disease · 年份：2023 · DOI：10.1002/jimd.12617 · 被引用次数：36 · 研究领域：Metabolism and Genetic Disorders、Mitochondrial Function and Pathology、Metabolomics and Mass Spectrometry Studies

Methylmalonic acidemia (MMA) is a severe inborn error of metabolism that is characterized by pleiotropic metabolic perturbations and multiorgan pathology. Treatment options are limited and non-curative as the underlying causative molecular mechanisms remain unknown. While earlier studies have focused on the potential direct toxicity of metabolites such as methylmalonic and propionic acid as a mechanism to explain disease pathophysiology, new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA and potentially reduced function of all three indicates aberrant acylation may require clinical intervention. Therefore, targeting posttranslational modifications may represent a new therapeutic approach to treat MMA and related organic acidemias.