Mmut-flox Mouse

MMUT, encoding methyl-malonyl coenzyme A mutase, is crucial in the metabolism of propionate. It catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, which is an important step in the catabolism of several amino acids, odd-chain fatty acids, and cholesterol. This process is part of the mitochondrial metabolism pathway and is essential for normal cellular function [3,4,6].

In methylmalonic acidemia (MMA), a disease associated with MMUT, different mutations in the MMUT gene have varying impacts. For instance, mutations like c.1663G>A, c.2080C>T, etc., are associated with complete responsiveness to vitamin B12 treatment in MMA patients, while mutations such as c.1741C>T, c.1630_1631GG>TA are related to partial responsiveness [1]. The c.1663G>A (p.A555T) mutation is relatively rare and in Chinese patients, those with this mutation showed later onset, milder clinical phenotypes, better vitamin B12 responsiveness, and better prognosis compared to those with other MMUT mutations [2]. A novel splice site variant c.2125-2A>G in the MMUT gene was found to cause a mild MMA phenotype, as it partially disrupts normal splicing but still allows for the production of a minor amount of full-length transcript [5]. Cellular models of MMUT-KO (MUTKO) clones, like immortalized fibroblast (hTERT BJ5ta) MUTKO clones, have shown a mild mitochondrial impairment and specific growth phenotypes under certain conditions, such as lower extracellular glutamine concentrations. This indicates that cells may compensate for the loss of MMUT function through increased anaplerosis via glutamine or by diverting flux away from MMUT through the secondary propionyl-CoA oxidation pathway [6].

In conclusion, MMUT is essential for normal mitochondrial metabolism, specifically in the propionate metabolism pathway. Research on MMUT, especially through cellular models and patient-based genetic studies, has significantly enhanced our understanding of methylmalonic acidemia. The identification of various MMUT mutations and their associated phenotypes, along with the insights from cellular KO models, provides valuable information for potential therapeutic strategies in treating MMA.