Development and characterization of a mouse model for Acad9 deficiency

Area of Science:

• Biochemistry
• Genetics
• Mitochondrial Biology

Background:

• Acyl CoA Dehydrogenase 9 (ACAD9) is crucial for mitochondrial fatty acid oxidation (FAO) and Complex I assembly.
• ACAD9 deficiency causes combined FAO and oxidative phosphorylation defects, leading to severe childhood morbidity and mortality.
• The dual role of ACAD9 in FAO and electron transport chain (ETC) complex I assembly is not fully understood.

Purpose of the Study:

• To investigate the physiological roles of ACAD9 and the pathophysiology of ACAD9 deficiency.
• To develop and utilize ACAD9 knockout mouse models for studying the disorder.

Main Methods:

• Generation of ACAD9 knockout mouse models using Cre-lox technology for tissue-specific deletion.
• Phenotypic analysis of cardiac-specific and muscle-specific ACAD9 deficient mice.
• Biochemical assessment of mitochondrial function and protein interactions (ECSIT) in mutant tissues.

Main Results:

• Total body ACAD9 knockout was lethal, indicating essentiality.
• Cardiac-specific ACAD9 deficiency resulted in neonatal cardiomyopathy and lethality by 17 days, with severe mitochondrial dysfunction.
• Muscle-specific ACAD9 deficiency led to viable but weak mice.
• Reduced ECSIT levels in cardiac-specific mutants confirmed impaired Complex I assembly.

Conclusions:

• ACAD9 is essential for both fatty acid oxidation and mitochondrial Complex I assembly.
• Tissue-specific ACAD9 deficiency models recapitulate key aspects of human disease.
• These mouse models provide valuable tools for therapeutic development for ACAD9 deficiency disorders.