Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy

EMBO Mol Med. 2019 Jan;11(1):e9288. doi: 10.15252/emmm.201809288.


Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i-AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin-like GTPase OPA1. Mutations in YME1L cause a multi-systemic mitochondriopathy associated with neurological dysfunction and mitochondrial fragmentation but pathogenic mechanisms remained enigmatic. Here, we report on striking cell-type-specific defects in mice lacking YME1L in the nervous system. YME1L-deficient mice manifest ocular dysfunction with microphthalmia and cataracts and develop deficiencies in locomotor activity due to specific degeneration of spinal cord axons, which relay proprioceptive signals from the hind limbs to the cerebellum. Mitochondrial fragmentation occurs throughout the nervous system and does not correlate with the degenerative phenotype. Deletion of Oma1 restores tubular mitochondria but deteriorates axonal degeneration in the absence of YME1L, demonstrating that impaired mitochondrial proteostasis rather than mitochondrial fragmentation causes the observed neurological defects.

Keywords: OMA1; YME1L; axonal degeneration; microphthalmia; mitochondrial proteostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / deficiency*
  • Animals
  • Cataract / etiology
  • Cataract / pathology
  • Disease Models, Animal
  • GTP Phosphohydrolases / metabolism
  • Gait Disorders, Neurologic / etiology
  • Gait Disorders, Neurologic / pathology
  • Metalloendopeptidases / deficiency*
  • Mice
  • Microphthalmos / etiology
  • Microphthalmos / pathology
  • Mitochondrial Diseases / pathology*
  • Mitochondrial Diseases / physiopathology*
  • Mitochondrial Proteins / deficiency
  • Nervous System Diseases / pathology*
  • Nervous System Diseases / physiopathology*
  • Spinal Cord / pathology


  • Mitochondrial Proteins
  • Metalloendopeptidases
  • YME1L protein, mouse
  • GTP Phosphohydrolases
  • Opa1 protein, mouse
  • ATPases Associated with Diverse Cellular Activities