Bianca Hartmann, Timothy Wai, Hao Hu, Thomas MacVicar, Luciana Musante, Björn Fischer-Zirnsak, Werner Stenzel, Ralph Gräf, Lambert van den Heuvel, Hans-Hilger Ropers, Thomas F. Wienker, Christoph Hübner, Thomas Langer, Angela M. Kaindl
- Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrialMitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.…
MetadatenVerfasserangaben: | Bianca Hartmann, Timothy Wai, Hao Hu, Thomas MacVicar, Luciana Musante, Björn Fischer-Zirnsak, Werner Stenzel, Ralph GräfORCiDGND, Lambert van den Heuvel, Hans-Hilger Ropers, Thomas F. Wienker, Christoph Hübner, Thomas Langer, Angela M. Kaindl |
---|
DOI: | https://doi.org/10.7554/eLife.16078 |
---|
ISSN: | 2050-084X |
---|
Titel des übergeordneten Werks (Englisch): | eLife |
---|
Verlag: | eLife Sciences Publications |
---|
Verlagsort: | Cambridge |
---|
Publikationstyp: | Wissenschaftlicher Artikel |
---|
Sprache: | Englisch |
---|
Jahr der Erstveröffentlichung: | 2016 |
---|
Erscheinungsjahr: | 2016 |
---|
Datum der Freischaltung: | 22.03.2020 |
---|
Freies Schlagwort / Tag: | OPA1; YME1L1; intellectual disability; mitochondrial fragmentation; mitochondriopathy; optic atrophy |
---|
Band: | 5 |
---|
Seitenanzahl: | 37 |
---|
Erste Seite: | 1156 |
---|
Letzte Seite: | 1165 |
---|
Fördernde Institution: | German Research Foundation [SFB665, KO2891/1-1]; Berlin Institute of Health (BIH) [CRG1]; Sonnenfeld Stiftung; German Society for Muscle diseases (DGM); German Academic Exchange Service (DAAD); NCRR [P20-RR016453]; Robert C. Perry Fund [20061479]; Max-Planck Society; EU [241995]; Human Frontiers Science Program |
---|
Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
---|
Peer Review: | Referiert |
---|