UNASSIGNED: Dysfunctions in mitochondrial complex I ( @entity2125 : @entity12931 oxidoreductase) are both genetically and clinically highly diverse and a major cause of @entity1 @entity2383 . The genetic determinants of individual clinical cases are increasingly being described, but how these @entity74 affect complex I on the molecular and cellular level, and have different clinical consequences in different individuals, is little understood. Furthermore, without molecular-level information innocent genetic variants may be misassigned as pathogenic. Here, we have used a @entity375 model system ( @entity10057 ) to study the molecular consequences of 16 single @entity3689 substitutions, classified as pathogenic, in the NDUFV1 subunit of complex I. NDUFV1 binds the @entity1785 cofactor that oxidizes @entity2125 and is the site of complex I-mediated reactive @entity26 species production. Seven mutations caused loss of complex I expression, suggesting they are detrimental but precluding further study. In two variants complex I was fully assembled but did not contain any @entity1785 , and four mutations led to functionally compromised enzymes. Our study provides a molecular rationale for assignment of all these variants as pathogenic. However, three variants provided complex I that was functionally equivalent to the wild-type enzyme, challenging their assignment as pathogenic. By combining structural, bioinformatic and functional data, a simple scoring system for the initial evaluation of future NDUFV1 variants is proposed. Overall, our results broaden understanding of how mutations in this centrally important core subunit of complex I affect its function and provide a basis for understanding the role of NDUFV1 mutations in @entity2383 .

Characterization of clinically identified mutations in NDUFV1, the @entity1785 -binding subunit of respiratory complex I, using a XXXX model system.

@entity1 :: ('9606', 'Species') :: ['human'] @entity2125 :: ('MESH:D009243', 'Chemical') :: ['NADH'] @entity12931 :: ('MESH:D014451', 'Chemical') :: ['ubiquinone'] @entity1785 :: ('MESH:C024132', 'Chemical') :: ['flavin'] @entity26 :: ('MESH:D010100', 'Chemical') :: ['oxygen'] @entity74 :: ('MESH:D030342', 'Disease') :: ['genetic defects'] @entity375 :: ('4932', 'Species') :: ['yeast'] @entity3689 :: ('D000596', 'Chemical') :: ['amino acid'] @entity10057 :: ('4952', 'Species') :: ['Yarrowia lipolytica'] @entity2383 :: ('MESH:D028361', 'Disease') :: ['mitochondrial dysfunction', 'mitochondrial diseases']
@entity375 :: (4932,Species) :: ['yeast']
