Exercise intolerance and developmental delay associated with a novel mitochondrial ND5 mutation.

Area of Science:

• Genetics and Molecular Biology
• Cellular Respiration
• Mitochondrial Diseases

Background:

• Oxidative phosphorylation (OXPHO) deficiency is a group of debilitating mitochondrial diseases.
• Identifying causative mitochondrial DNA (mtDNA) mutations is crucial for diagnosis and understanding disease mechanisms.

Observation:

• Screening of 41 families with OXPHO deficiency identified a novel mtDNA mutation: m.12955A > G in the NADH dehydrogenase 5 (ND5) gene.
• This mutation was found in a patient presenting with exercise intolerance and developmental delay.

Findings:

• Biochemical analysis revealed deficiencies in Complex I and Complex IV activities in the patient.
• Functional studies in cybrid cells confirmed that the m.12955A > G mutation impairs Complex I assembly, destabilizes Complex IV, reduces OXPHO coupling and ATP generation.
• Increased reactive oxygen species (ROS) and lactate levels were observed in cells with higher mutant loads.

Implications:

• The m.12955A > G mutation is identified as a novel cause of mitochondrial disease.
• Screening for this mutation is recommended for patients with suspected mitochondrial disorders, particularly those with exercise intolerance and developmental delay.