Phenotypic convergence at mitochondria in copy number variant disorders

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PROJECT SUMMARY/ABSTRACT Substantial progress in psychiatric genomics has led to the identification of several copy number variants (CNVs) and single genes that are associated with extremely high risk for schizophrenia. A major question facing the field now is whether these discrete genomic loci all act independently or disrupt a common set of neurobiological pathways to produce a similar clinical phenotype. Studies on the effects of the 3q29 deletion, a CNV that confers >40-fold increased risk for schizophrenia, indicate that mitochondrial function may be disrupted in the developing central nervous system. Strikingly, the CNV with the next strongest risk for schizophrenia (22q11.2Del) has also been reported to produce mitochondrial phenotypes. In addition to the 3q29 and 22q11.2 deletion, at least nine other neurodevelopmental disorder-associated CNV loci also contain genes that encode mitochondrial proteins. These data motivate the hypothesis that neural mitochondria may be a site of convergent biology downstream of schizophrenia-risk CNVs. This career development project is designed to address this hypothesis with extensive new training in mitochondrial neurobiology. I have developed a unique set of isogenic human induced pluripotent stem cell lines that, in combination with mouse experimental models of each CNV, will be leveraged to test the hypothesis that 3q29 and 22q11.2 deletion similarly disrupt mitochondrial function in the developing nervous system. The goals of this project are to define the extent of mitochondrial phenotypes produced by these schizophrenia-associated CNVs and to determine the degree of biological convergence at molecular and functional levels. To this end we will assess the effects of each CNV on the proteome of mitochondria isolated from CNV-model mouse brain and isogenic human cortical organoids. Additionally, the transition from glycolysis to oxidative phosphorylation is a critical stage of neuronal development. We will test the capacity of 3q29 deletion and 22q11.2 deletion neural progenitor cells to adapt to metabolic stress by using media formulations to force cultures to either utilize glycolysis or oxidative phosphorylation to meet energy demands. Finally, we will utilize an engineered heterologous cell system to screen for gene drivers of 3q29 mitochondrial phenotypes. These experiments will yield important data related to the concept of convergent biology, a timely and significant question in translational psychiatry which could have profound effects on our understanding of risk alleles and future therapeutic approaches.