© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.The congenital disorder 22q11.2 deletion syndrome, characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder and the second risk factor for schizophrenia. Nine of - 30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism. Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neur…
Read more© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.The congenital disorder 22q11.2 deletion syndrome, characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder and the second risk factor for schizophrenia. Nine of - 30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism. 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 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 accompanied by an increase in reductive carboxylation of α-ketoglutarate. 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.