Sprenger, Hans-Georg, Wani, Gulzar, Hesseling, Annika, Koenig, Tim, Patron, Maria, MacVicar, Thomas, Ahola, Sofia, Wai, Timothy, Barth, Esther, Rugarli, Elena I., Bergami, Matteo ORCID: 0000-0001-5525-5025 and Langer, Thomas (2019). Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy. EMBO Mol. Med., 11 (1). HOBOKEN: WILEY. ISSN 1757-4684

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sprenger, Hans-GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wani, GulzarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hesseling, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patron, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacVicar, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahola, SofiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wai, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barth, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rugarli, Elena I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergami, MatteoUNSPECIFIEDorcid.org/0000-0001-5525-5025UNSPECIFIED
Langer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-140209
DOI: 10.15252/emmm.201809288
Journal or Publication Title: EMBO Mol. Med.
Volume: 11
Number: 1
Date: 2019
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1757-4684
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOUSE MODEL; OPTIC ATROPHY; CELL-DEATH; OPA1; FUSION; OMA1; STRESS; DYNAMICS; CRISTAE; NEURODEGENERATIONMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14020

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