Investigation into Tissue-Specific Mechanisms of Mitochondrial Dysfunction: Models of SUCLA2 Deficiency and a Screen for Potential Genetic Modifiers
type: CreativeWork
description: With no currently effective treatments available, mitochondrial diseases are one of the most common forms of inherited multisystem disease. Primary disorders of the mitochondria affect an estimated 1 in 4,300 people with typical onset in early childhood. Mitochondrial disorders are classically defined by defects in the mitochondrial powerhouse, or respiratory chain (RC). Therefore, they are uniquely complex as the proteins within the RC are encoded by two separate genomes – nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). The mitochondrial genome encodes 13 protein genes within the RC, with the remaining mitochondrial proteome being nuclear encoded. Therefore, mitochondrial disorders result from pathogenic variants within either genome. While mitochondrial disorders can affect multiple tissue symptoms, organs with high energy demand, such as the brain and skeletal muscle, are most typically affected; thus, mitochondrial disease typically manifests as an encephalomyopathy. A wide range of symptoms, including developmental delay, seizures, strokes, and sensorineural hearing loss have been associated with mitochondrial dysfunction. In short, however, investigation into the pathogenic mechanisms of mitochondrial disorders has proven difficult due to the wide clinical and genetic heterogeneity associated with the disorders. Therefore, this project seeks to investigate pathways of mitochondrial dysfunction using two genetic approaches. First, reverse genetics tools are used to generate tissue-specific mouse models of succinyl-CoA synthetase deficiency, which is a known cause of mitochondrial disease in humans. In parallel, forward genetics is used to screen for variation in mitochondrial phenotypes in a genetically diverse population of mice to identify potential genetic modifiers of mitochondrial function and health. Using both forward and reverse genetics approaches, these studies will allow for the investigation into tissue-specific mitochondrial pathogenesis in novel…
abstract: With no currently effective treatments available, mitochondrial diseases are one of the most common forms of inherited multisystem disease. Primary disorders of the mitochondria affect an estimated 1 in 4,300 people with typical onset in early childhood. Mitochondrial disorders are classically defined by defects in the mitochondrial powerhouse, or respiratory chain (RC). Therefore, they are uniquely complex as the proteins within the RC are encoded by two separate genomes – nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). The mitochondrial genome encodes 13 protein genes within the RC, with the remaining mitochondrial proteome being nuclear encoded. Therefore, mitochondrial disorders result from pathogenic variants within either genome. While mitochondrial disorders can affect multiple tissue symptoms, organs with high energy demand, such as the brain and skeletal muscle, are most typically affected; thus, mitochondrial disease typically manifests as an encephalomyopathy. A wide range of symptoms, including developmental delay, seizures, strokes, and sensorineural hearing loss have been associated with mitochondrial dysfunction. In short, however, investigation into the pathogenic mechanisms of mitochondrial disorders has proven difficult due to the wide clinical and genetic heterogeneity associated with the disorders. Therefore, this project seeks to investigate pathways of mitochondrial dysfunction using two genetic approaches. First, reverse genetics tools are used to generate tissue-specific mouse models of succinyl-CoA synthetase deficiency, which is a known cause of mitochondrial disease in humans. In parallel, forward genetics is used to screen for variation in mitochondrial phenotypes in a genetically diverse population of mice to identify potential genetic modifiers of mitochondrial function and health. Using both forward and reverse genetics approaches, these studies will allow for the investigation into tissue-specific mitochondrial pathogenesis in novel…
author: Lancaster, Makayla S.
language: en_US
keywords: Brain, Mitochondria, Muscle, Succinyl-CoA synthetase, Succinylation, Tricarboxylic acid cycle
date published: 2023-11
date modified: 2026-07-24T02:41:19Z
provider: IUPUI
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: IUPUI

PropertyValue
property ID: Handle
value: https://hdl.handle.net/1805/37280

PropertyValue
property ID: DOI
value: 10.7912/TN11-RA53