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Alterations in the carnitine cycle in a mouse model of Rett syndrome
Sabrina Mucerino1, Anna Di Salle1, Nicola Alessio2
1Institute of Bioscience and BioResources, CNR, Naples, Italy.
Abstract:
Rett syndrome (RTT) is a neurodevelopmental disease that leads to intellectual deficit, motor disability, epilepsy and increased risk of sudden death. Although in up to 95% of cases this disease is caused by de novo loss-of-function mutations in the X-linked methyl-CpG binding protein 2 gene, it is a multisystem disease associated also with mitochondrial metabolic imbalance. In addition, the presence of long QT intervals (LQT) on the patients' electrocardiograms has been associated with the development of ventricular tachyarrhythmias and sudden death. In the attempt to shed light on the mechanism underlying heart failure in RTT, we investigated the contribution of the carnitine cycle to the onset of mitochondrial dysfunction in the cardiac tissues of two subgroups of RTT mice, namely Mecp2+/- NQTc and Mecp2+/- LQTc mice, that have a normal and an LQT interval, respectively. We found that carnitine palmitoyltransferase 1 A/B and carnitine acylcarnitine translocase were significantly upregulated at mRNA and protein level in the heart of Mecp2+/- mice. Moreover, the carnitine system was imbalanced in Mecp2+/- LQTc mice due to decreased carnitine acylcarnitine transferase expression. By causing accumulation of intramitochondrial acylcarnitines, this imbalance exacerbated incomplete fatty acid oxidation, which, in turn, could contribute to mitochondrial overload and sudden death.
Insights
Rett syndrome (RTT) involves mitochondrial dysfunction and heart failure, linked to carnitine cycle imbalances. This study reveals how these imbalances in RTT mice exacerbate fatty acid oxidation issues, potentially causing sudden death.
Area of Science:
- Biochemistry
- Genetics
- Cardiology
Background:
- Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 gene mutations.
- RTT is a multisystem disease associated with mitochondrial dysfunction and cardiac issues, including long QT intervals (LQT) and sudden death.
- The carnitine cycle is crucial for cardiac fatty acid metabolism and mitochondrial function.
Purpose of the Study:
- To investigate the carnitine cycle's role in cardiac mitochondrial dysfunction in RTT mouse models.
- To compare carnitine system function in RTT mice with normal (NQTc) and long QT intervals (LQTc).
Main Methods:
- Analysis of carnitine cycle enzyme expression (mRNA and protein) in cardiac tissues of Mecp2+/- NQTc and Mecp2+/- LQTc mice.
- Assessment of carnitine system balance and its impact on fatty acid oxidation.
Main Results:
- Carnitine palmitoyltransferase 1A/B and carnitine acylcarnitine translocase were upregulated in Mecp2+/- mouse hearts.
- The carnitine system was imbalanced in Mecp2+/- LQTc mice due to reduced carnitine acylcarnitine transferase expression.
- This imbalance led to intramitochondrial acylcarnitine accumulation, impaired fatty acid oxidation, and potential mitochondrial overload.
Conclusions:
- Carnitine cycle dysfunction contributes to mitochondrial overload and heart failure in RTT.
- Imbalances in the carnitine system, particularly in LQTc RTT mice, exacerbate metabolic defects and may increase sudden death risk.
