NDUFA9 point mutations cause a variable mitochondrial complex I assembly defect.

Area of Science:

• Mitochondrial biology and genetics
• Neurodegenerative diseases
• Human genetics and genomics

Background:

• Mitochondrial respiratory chain complex I is crucial for cellular energy production, composed of three modules: Q, N, and P.
• NDUFA9, a Q-module subunit, is essential for complex I assembly and stability, but its precise role in biogenesis remains unclear.
• Previous studies reported a severe phenotype in a single patient with an NDUFA9 variant.

Observation:

• Exome sequencing identified a novel homozygous NDUFA9 missense variant in a patient with childhood-onset dystonia and neuropathy.
• Fibroblast analysis revealed reduced complex I abundance and Q-module subassembly accumulation in both severe and mild NDUFA9 deficiency patients.
• The severe phenotype patient showed additional P-module subassembly accumulation, absent in the mild case.

Findings:

• Both NDUFA9 variants led to complex I deficiency and assembly defects, with varying severity correlating to clinical presentation.
• Lentiviral complementation with wild-type NDUFA9 successfully rescued complex I deficiency and assembly defects in patient fibroblasts.
• The study establishes a correlation between the severity of NDUFA9 variants, their impact on complex I assembly, and the clinical phenotype.

Implications:

• This research expands the known phenotypic spectrum of NDUFA9 deficiency, highlighting its role in progressive neurological disorders.
• The findings underscore the importance of NDUFA9 in complex I biogenesis and provide insights into genotype-phenotype correlations.
• Understanding these mechanisms could pave the way for targeted therapeutic strategies for mitochondrial complex I-related diseases.