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Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions
Michele Costanzo1,2, Armando Cevenini3,4, Laxmikanth Kollipara5
1Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, Naples, 80131, Italy. michele.costanzo@unina.it.
Cell & Bioscience
|May 17, 2024
Summary
Methylmalonic acidemia (MMA), caused by methylmalonyl-CoA mutase (MUT) deficiency, disrupts cell metabolism. This study reveals MMA impairs lysosome and autophagy function, offering new therapeutic targets.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Methylmalonic acidemia (MMA) is a rare metabolic disorder.
- It stems from methylmalonyl-CoA mutase (MUT) enzyme deficiency.
- MMA causes significant cellular damage impacting multiple pathways.
Purpose of the Study:
- To investigate novel pathological mechanisms in MUT deficiency.
- To explore the connection between MMA and cellular component dysfunction.
- To utilize multi-omics and bioinformatics for deeper insights.
Main Methods:
- Employed cellular models and patient-derived fibroblasts.
- Conducted multi-proteomics and bioinformatics analyses.
- Assessed lysosome morphology and function in MMA cells.
Main Results:
- MUT deficiency causes widespread proteome dysregulation.
- Lysosomes in MMA cells are enlarged with impaired degradative capacity.
- Treatment with an anti-propionigenic drug restored lysosomal function.
Conclusions:
- MMA leads to defective regulation of autophagy and lysosome homeostasis.
- The study demonstrates impaired autophagosome-lysosome fusion and lysosomal activity in MMA.
- Findings suggest a direct link between MUT deficiency and lysosomal-autophagy dysfunction.
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