Multiomics Analysis of Mitochondrial, autophagic, and lysosomal Balance in cblC methylmalonic Acidemia (MAMBA)

Methylmalonic acidemia and homocystinuria, cblC type is a rare genetic disorder caused by mutations in the MMACHC gene, affecting around 1 in 200,000 newborns. This condition impacts how the body processes vitamin B12, leading to the accumulation of harmful substances like methylmalonic acid and homocysteine, and a reduction in methionine levels. Symptoms can appear early in life or later, and include developmental delays, neurological issues, vision loss, and cardiovascular complications. Despite existing treatments, such as vitamin B12 injections and dietary adjustments, many patients continue to experience disease progression, highlighting the need for better therapies. The present project aims to understand the underlying cellular mechanisms that cause cblC disease, focusing on processes like lysosomal function and autophagy impairment. Recent studies suggest these processes may be altered in similar metabolic disorders, contributing to cellular damage. We will use advanced multi-omics techniques—studying proteins, metabolites, and lipids—to compare diseased and healthy cells, identifying changes in these pathways. By uncovering how lysosomal and autophagic dysfunctions contribute to the disease, we hope to reveal new therapeutic targets. The goal of project will be to determine if these cellular impairments are a common feature in different types of methylmalonic acidemia and how they relate to known problems, such as mitochondrial defects and oxidative stress. This research could open the way to innovative treatments, improving outcomes and quality of life for patients with cblC disease.