title: Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome.
abstract: The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of ∼30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of α-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1α, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype.
authors.affiliation: From the Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, California 95616.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Napoli
authors.affiliation: the Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, the Department of Biochemistry and Molecular Medicine, School of Medicine, UC Davis, Sacramento, California 95817.
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.affiliation: From the Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, California 95616.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.affiliation: the Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, the Department of Pediatrics, and.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Angkustsiri
authors.affiliation: the Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, the Department of Psychiatry, UC Davis Medical Center, Sacramento, California 95817, and.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Simon
authors.affiliation: From the Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, California 95616.
authors.forename: Gyu
authors.initials: G
authors.lastname: Song
authors.affiliation: From the Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, California 95616, the Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, cgiulivi@ucdavis.edu.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics / Q000378:metabolism; D004062:DiGeorge Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters; D010085:Oxidative Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D002352:Carrier Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C489427:MYC protein, human; D024101:Mitochondrial Proteins; D027361:Organic Anion Transporters; D016271:Proto-Oncogene Proteins c-myc; C532592:Slc25a1 protein, human; C020723:citrate-binding transport protein
keywords: OXPHOS; bioenergetics; citrate transporter; epigenetics; metabolomics; mitochondria; mtDNA copy number; schizophrenia