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.
Highlights
Level of L-carnitine in some Rett syndrome (RTT) patients[18] and in patients with other autism spectrum disorders[20], carnitine deficiency has been implicated in the pathogenesis of heart dysfunction in RTT patients
These conflicting results are compatible with the concept that it is a perturbation of the carnitine system rather than a carnitine deficiency per se that is involved in the pathogenesis of heart failure in RTT patients
The upregulation of mitochondrial CPT1, carnitine acylcarnitine translocase (CACT) and CPT2 associated with downregulation of carnitine acetylcarnitine transferase (CRAT) found in the LQT RTT subgroup of mice could impair metabolic flexibility, which is required for maintenance of normal cardiac function
Summary
To determine if the mitochondrial dysfunction in heart tissue might involve the carnitine system, we investigated Cpt1a, Cpt1b, Cpt[2], Cact and CrAT expression and functionality in the explanted heart of Mecp2+/− NQTc and Mecp2+/− LQTc mice. The analysis of enzyme activity on mitochondrial enriched fractions isolated from heart tissues of Mecp2+/− NQTc and Mecp2+/− LQTc mice confirmed an increase in CPT1 and CACT and a loss of function of CrAT activity compared to WT mice (Fig. 1b). Concentrations of mitochondrial acetyl-CoA were significantly higher in both Mecp2+/− NQTc and Mecp2+/− LQTc mice than in WT mice. In the absence of pyruvate (basal condition), mitochondrial fatty acid oxidation to CO2 was lower, and incomplete oxidation to ASMs was higher in Mecp2+/− NQTc and Mecp2+/− LQTc mice than in WT mice. Taken together these results indicate that Mecp2+/− LQTc mice were unable to switch their metabolism correctly according to substrate availability, thereby leading to mitochondrial dysfunction and imbalance
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