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Elife. 2016 Aug 6;5. pii: e16078. doi: 10.7554/eLife.16078.

Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation.

Author information

1
Institute of Cell Biology and Neurobiology, Charité University Medicine, Berlin, Germany.
2
Department of Pediatric Neurology, Charité University Medicine, Berlin, Germany.
3
Sozialpädiatrisches Zentrum (SPZ), Center for Chronically Sick Children, Charité University Medicine, Berlin, Germany.
4
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
5
Max Planck Institute for Molecular Genetics, Berlin, Germany.
6
Guangzhou Women and Children's Medical Center, Guangzhou, China.
7
Institut of Medical Genetics and Human Genetics, Charité University Medicine, Berlin, Germany.
8
Institute of Neuropathology, Charité University Medicine, Berlin, Germany.
9
Department of Cell Biology, University of Potsdam, Potsdam, Germany.
10
Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, Netherlands.

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.

KEYWORDS:

OPA1; YME1L1; human; human biology; intellectual disability; medicine; mitochondrial fragmentation; mitochondriopathy; mouse; optic atrophy

PMID:
27495975
PMCID:
PMC4991934
DOI:
10.7554/eLife.16078
[Indexed for MEDLINE]
Free PMC Article

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