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Updated: May 23, 2025
08:19
Assessing Mitochondrial Function in Sciatic Nerve by High-Resolution Respirometry
Published on: May 5, 2022
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Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria
Matthew C S Denley1, Monique S Straub1, Giulio Marcionelli1
1Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, CH-8032, Switzerland.
Communications Biology
|March 12, 2025
Summary
Methylmalonic aciduria (MMA) causes mitochondrial dysfunction in neurons due to MMUT deficiency. This study models MMA using patient stem cells, revealing neuronal excitability alterations and paving the way for new brain treatments.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Stem Cell Biology
Background:
- Methylmalonic aciduria (MMA) is a metabolic disorder impacting the central nervous system.
- The precise mechanisms of neurological damage in MMA remain unclear, hindering effective brain-specific therapies.
Purpose of the Study:
- To develop and characterize a human neuronal model of MMA using patient-derived induced pluripotent stem cells.
- To investigate the underlying causes of neurological dysfunction in MMA at the cellular and molecular level.
Main Methods:
- Generation of patient-derived induced pluripotent stem cell lines.
- In vitro differentiation into human neurons.
- Patch-clamp electrophysiology for assessing neuronal excitability.
- Targeted metabolomics and bulk transcriptomics for molecular profiling.
Main Results:
- Demonstrated significant mitochondrial dysfunction in MMA patient-derived neurons due to methylmalonyl-CoA mutase (MMUT) deficiency.
- Identified altered neuronal excitability, which was worsened by dimethyl-2-oxoglutarate.
- Observed potential metabolic rewiring contributing to neuronal dysfunction.
Conclusions:
- This study provides the first evidence of mitochondrial-driven neuronal dysfunction in MMA.
- The developed human neuronal model offers a platform for understanding MMA pathogenesis and developing targeted therapies for brain-related symptoms.
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