title: Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation.
abstract: 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 mitochondrial functionality in humans.
authors: Institute of Cell Biology and Neurobiology, Charité University Medicine, Berlin, Germany.|Department of Pediatric Neurology, Charité University Medicine, Berlin, Germany.|Sozialpädiatrisches Zentrum (SPZ), Center for Chronically Sick Children, Charité University Medicine, Berlin, Germany.
authors: Bianca
authors: B
authors: Hartmann
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
authors: Timothy
authors: T
authors: Wai
authors: Max Planck Institute for Molecular Genetics, Berlin, Germany.|Guangzhou Women and Children's Medical Center, Guangzhou, China.
authors: Hao
authors: H
authors: Hu
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
authors: Thomas
authors: T
authors: MacVicar
authors: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors: Luciana
authors: L
authors: Musante
authors: Max Planck Institute for Molecular Genetics, Berlin, Germany.|Institut of Medical Genetics and Human Genetics, Charité University Medicine, Berlin, Germany.
authors: Björn
authors: B
authors: Fischer-Zirnsak
authors: Institute of Neuropathology, Charité University Medicine, Berlin, Germany.
authors: Werner
authors: W
authors: Stenzel
authors: Department of Cell Biology, University of Potsdam, Potsdam, Germany.
authors: Ralph
authors: R
authors: Gräf
authors: Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, Netherlands.
authors: Lambert
authors: L
authors: van den Heuvel
authors: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors: Hans-Hilger
authors: HH
authors: Ropers
authors: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors: Thomas F
authors: TF
authors: Wienker
authors: Department of Pediatric Neurology, Charité University Medicine, Berlin, Germany.
authors: Christoph
authors: C
authors: Hübner
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
authors: Thomas
authors: T
authors: Langer
authors: Institute of Cell Biology and Neurobiology, Charité University Medicine, Berlin, Germany.|Department of Pediatric Neurology, Charité University Medicine, Berlin, Germany.|Sozialpädiatrisches Zentrum (SPZ), Center for Chronically Sick Children, Charité University Medicine, Berlin, Germany.
authors: Angela M
authors: 0000-0001-9454-206X
authors: AM
authors: Kaindl
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D008928:Mitochondria / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; D008666:Metalloendopeptidases; C410807:YME1L1 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities
keywords: OPA1; YME1L1; human; human biology; intellectual disability; medicine; mitochondrial fragmentation; mitochondriopathy; mouse; optic atrophy