# Determination of pathogenetic mechanisms in cortex-specific Sucla2 deficiency as a model for mitochondrial encephalopathy

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $504,093

## Abstract

Abstract
Mitochondrial encephalomyopathy with mitochondrial DNA (mtDNA) depletion is a class of
mitochondrial disease that causes neurological dysfunction with intellectual and developmental
disabilities and myopathy. Deficiency of ADP-specific succinyl-CoA synthetase (SCS), a
component of the TCA cycle, is one of the causes of mitochondrial encephalomyopathy with
mtDNA depletion. SCS is an important integration point of the TCA cycle, intersecting energy
metabolism and posttranslational succinylation. Previous studies have demonstrated that
embryonic mice homozygous for a constitutive mutant Sucla2 allele are embryonic lethal and
exhibit ADP-specific SCS deficiency and mtDNA depletion with detrimental effects on energy
metabolism. For this proposal, to generate adult Sucla2 deficient animals, a conditional
knockout strategy of Sucla2 limited to the postnatal forebrain is employed. Initial investigations
reveal that the mutant animals exhibit a defect in learning and memory and perturbations of
energy metabolism and global protein succinylation in the cortex in the absence of mtDNA
depletion. This proposal is based on the hypothesis that adult phenotypes of Sucla2
deficiency are caused by a combination of TCA cycle dysfunction and perturbations of
global posttranslational succinylation. The Sucla2-forebrain knockout model will be
analyzed by a targeted battery of behavioral assays designed to fully characterize different
cognitive domains for deficits. To determine the potential differential effects of developmental
timing of Sucla2 loss, a conditional knockout with prenatal onset of Sucla2 deficiency will also
be generated and subjected to longitudinal broad behavioral and in vivo physiological screening,
including basic motor, autonomic, sensory, and cognitive assays in both adolescent and adult
stages. Cortex from the forebrain conditional knockout model will be analyzed for
histopathological changes, metabolomic alterations, TCA and ETC enzyme activities, global
posttranslational succinylation and mtDNA content. An innovative approach using integrated
single nuclear (sn) RNA-seq and snATAC-seq to identify differential gene expression patterns
and alterations in chromatin accessibility landscape in different cortical cell types defined by
distinct expression clusters will be employed and the datasets used to inform histopathological
and metabolomic analyses. These studies will provide insights into the pathogenic mechanisms
of Sucla2/SCS deficiency and establish a preclinical model to explore and develop novel
therapeutic approaches.

## Key facts

- **NIH application ID:** 10850591
- **Project number:** 5R01NS126597-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Brett Harrison Graham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $504,093
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850591

## Citation

> US National Institutes of Health, RePORTER application 10850591, Determination of pathogenetic mechanisms in cortex-specific Sucla2 deficiency as a model for mitochondrial encephalopathy (5R01NS126597-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10850591. Licensed CC0.

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