# Phenotypic convergence at mitochondria in copy number variant disorders

> **NIH NIH K01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $143,416

## Abstract

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
(22q11Del) 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 3q29Del 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.

## Key facts

- **NIH application ID:** 11241925
- **Project number:** 7K01MH133970-03
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Ryan Herndon Purcell
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $143,416
- **Award type:** 7
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11241925

## Citation

> US National Institutes of Health, RePORTER application 11241925, Phenotypic convergence at mitochondria in copy number variant disorders (7K01MH133970-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11241925. Licensed CC0.

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