MMA produces unique protein modifications that contribute to disease

Dr. Charles Venditti’s lab at the National Institutes of Health has recently discovered a new protein modification in methylmalonic acidemia (MMA) that drives disease pathology. The work of postdoctoral researcher, Dr. PamelaSara Head, in a recent article published in Science Translational Medicine, demonstrated how the build-up of methylmalonyl-CoA (the substance converted to methylmalonic acid in MMA patients) can also lead to the build-up of a new type of modification of enzymes in liver, kidney, and brain cells. They have termed this modification “methylmalonylation”. Too much methylmalonylation modification on enzymes upsets their normal function often by turning the enzyme off when it should be on or vice versa. 

Many of the affected enzymes are located in or around the cell mitochondria and when modified can result in MMA symptoms such as hyperammonemia (buildup of ammonia in the blood), hyperglycinemia (buildup of glycine), and poor cellular use of sugar and low energy production. These results were seen in the lab’s mouse models of MMA and more importantly, were confirmed in donated MMA liver tissue from MMA patients who received liver transplants. These discoveries uncovered a mechanism behind the high ammonia and glycine levels that are typically seen in severe MMA and provided deeper insights as to why patients still experience disease symptoms even with around the clock care with protein restricted diets and formulas as well as medical monitoring.   

During this study, Dr. Head also discovered which enzyme is responsible for removing the disruptive methylmalonylation modifications. This enzyme is known as SIRT5 and it helps maintain mitochondrial health (keep mitochondria healthy/functioning). After discovering that SIRT5 levels are naturally lower in MMA tissues and determining that SIRT5 itself can also be modified by methylmalonylation, Dr. Head engineered a new version of the SIRT5 protein to escape the abnormal modification and maintain its activity. This “SuperSIRT5” was given to affected MMA mice using a gene therapy called adeno-associated virus (AAV). Treated mice had lower methylmalonylation modifications, increased weight gain, lower blood ammonia levels and restoration of other mitochondrial health markers. 

Overall, the discoveries by the Venditti lab provide insight into symptom development not just in MMA but potentially in other organic acidemias (OAs) and forms of vitamin B12 deficiency and provide a novel therapeutic target to pursue for future drug development.       

For more information you can read the article here: https://pubmed.ncbi.nlm.nih.gov/35613279/

And the supporting article by Dr. Goetzman and Dr. Vockley here: 
https://pubmed.ncbi.nlm.nih.gov/35613282/

We appreciate all the families that have participated in our studies over the years. This study would not have been possible without the families who donated their precious liver samples to our research. More information about our research can be found here: 
https://www.genome.gov/staff/Charles-P-Venditti-MD-PhD