Reference - Detail
| RRC ID | 88103 |
|---|---|
| Author | Fielder SM, Friederich MW, Hock DH, Zhang JR, Valin LM, Rosenfeld JA, Booth KTA, Brown NJ, Rius R, Sharma T, Semcesen LN, Worley KC, Burrage LC, Treat K, Samson T, Govert S, DaCunha S, Yuan W, Chen J, Lesinski J, Hoang H, Morrison SA, Ladha FA, Van Hove RA, Michel CR, Reisdorph R, Tycksen E, Baldridge D, Silverman GA, Soler-Alfonso C, Conboy E, Vetrini F, Emrick L, Craigen WJ, Undiagnosed Diseases Network, Sykes SM, Stroud DA, Van Hove JLK, Schedl T, Pak SC. |
| Title | Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders. |
| Journal | EMBO Mol Med |
| Abstract |
ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency. |
| Volume | 17(10) |
| Pages | 2562-2585 |
| Published | 2025-10-1 |
| DOI | 10.1038/s44321-025-00290-8 |
| PII | 10.1038/s44321-025-00290-8 |
| PMID | 40859057 |
| PMC | PMC12514044 |
| MeSH | Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Child Child, Preschool Female Humans Male Mitochondria / metabolism Mitochondrial Proton-Translocating ATPases* / genetics Mitochondrial Proton-Translocating ATPases* / metabolism Mutation, Missense Nervous System Diseases* / genetics Nervous System Diseases* / pathology Oxidative Phosphorylation* |
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| The most frequently cited source | Podcasts |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tmC5 tmIs1220 |