Alterations in the carnitine cycle in a mouse model of Rett syndrome.
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.
Institute of Bioscience and BioResources, CNR, Naples, Italy.
Sabrina
S
Mucerino
Institute of Bioscience and BioResources, CNR, Naples, Italy.
Anna
A
Di Salle
Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania "Luigi Vanvitelli", Naples, Italy.
Nicola
N
Alessio
Institute of Bioscience and BioResources, CNR, Naples, Italy.
Sabrina
S
Margarucci
Sigma-tau S.p.A., Pomezia, Rome, Italy.
Raffaella
R
Nicolai
Department of Medical, Surgical, Neurological, Metabolic Sciences, and Aging; Division of Neurology and InterUniversity Center for Research in Neurosciences, University of Campania "Luigi Vanvitelli", Naples, Italy.
Mariarosa A B
MA
Melone
Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania "Luigi Vanvitelli", Naples, Italy.
Umberto
U
Galderisi
Institute of Bioscience and BioResources, CNR, Naples, Italy.
Gianfranco
G
Peluso
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D050172:Genes, X-Linked; D050356:Lipid Metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D055432:Metabolomics / Q000379:methods; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D010641:Phenotype; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*
D051783:Methyl-CpG-Binding Protein 2; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; C116917:acylcarnitine; D000105:Acetyl Coenzyme A; D002331:Carnitine