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.DOI: http://dx.doi.org/10.7554/eLife.16078.001

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

“…This results in impaired locomotor activity and hind limb paralysis of the mice starting at approximately 17 weeks of age. Our loss‐of‐function model for YME1L in the nervous system therefore recapitulates some clinical features of a neuromuscular disorder that is caused by homozygous missense mutations in YME1L and characterized by developmental delay, ocular dysfunction, ataxia and athetotic and stereotypic movements (Hartmann et al , ). Phenotypic differences between NYKO mice and human patients are likely explained by the hypomorphic character of the missense mutation in human (Hartmann et al , ).…”

“…Our loss-of-function model for YME1L in the nervous system therefore recapitulates some clinical features of a neuromuscular disorder that is caused by homozygous missense mutations in YME1L and characterized by developmental delay, ocular dysfunction, ataxia and athetotic and stereotypic movements (Hartmann et al, 2016). Phenotypic differences between NYKO mice and human patients are likely explained by the hypomorphic character of the missense mutation in human (Hartmann et al, 2016). Our results also uncover an unexpected role of YME1L for the development of the eye and point to a novel pathway triggering microphthalmia and cataracts in mitochondrial diseases, which is independent of respiratory dysfunction and highlights the importance of mitochondrial proteostasis for axonal maintenance in neurodegenerative disorders.…”

Structure of the mitochondrial inner membrane AAA+ protease YME1 gives insight into substrate processing

“…Similarly, genetic ablation of Yme1l1 is embryonic lethal and conditional deletion in adult cardiomyocytes causes heart failure and premature death in mice (13). Furthermore, homozygous mutation of Yme1l1 causes mitochondriopathy with optic nerve atrophy in humans (14). …”

Coordinating Mitochondrial Biology Through the Stress-Responsive Regulation of Mitochondrial Proteases

“…A potential role for PARL in PD could reflect the involvement of this protease in regulating the PINK1-Parkin mitophagy axis (Greene et al, 2012; Jin et al, 2010; Meissner et al, 2015; Yamano and Youle, 2013), which would be consistent with the link between PD and other proteins involved in this pathway (Youle and Narendra, 2011). YME1L1 mutations have also been found to be causatively associated with mitochondriopathy in familial optic atrophy (Hartmann et al, 2016). Here, mutations in the YME1L1 mitochondrial targeting sequence affect MPP-dependent maturation of the protease, decreasing YME1L proteolytic activity and disrupting mitochondrial morphology and function.…”