Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy
Abstract Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintain...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2021-02-01
|
Series: | Molecular Neurodegeneration |
Subjects: | |
Online Access: | https://doi.org/10.1186/s13024-021-00431-w |
id |
doaj-e7ccbd1244924e7b9928a8f0b2608ff1 |
---|---|
record_format |
Article |
spelling |
doaj-e7ccbd1244924e7b9928a8f0b2608ff12021-03-11T12:00:36ZengBMCMolecular Neurodegeneration1750-13262021-02-011611910.1186/s13024-021-00431-wDominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathyMajida Charif0Yvette C. Wong1Soojin Kim2Agnès Guichet3Catherine Vignal4Xavier Zanlonghi5Philippe Bensaid6Vincent Procaccio7Dominique Bonneau8Patrizia Amati-Bonneau9Pascal Reynier10Dimitri Krainc11Guy Lenaers12Université d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVascDepartment of Neurology, Northwestern University Feinberg School of MedicineDepartment of Neurology, Northwestern University Feinberg School of MedicineDepartments of Biochemistry and Genetics, University Hospital AngersNeuroophthalmology Department, Rothschild Ophthalmologic FoundationCentre de Compétence Maladies Rares, Clinique Pluridisciplinaire Jules VerneCabinet d’OphtalmologieUniversité d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVascUniversité d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVascUniversité d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVascUniversité d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVascDepartment of Neurology, Northwestern University Feinberg School of MedicineUniversité d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVascAbstract Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration.https://doi.org/10.1186/s13024-021-00431-wMitochondria dynamicsMitochondrial diseaseMIEF1Mid51Dominant optic atrophy (DOA)Inherited optic neuropathy (ION) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Majida Charif Yvette C. Wong Soojin Kim Agnès Guichet Catherine Vignal Xavier Zanlonghi Philippe Bensaid Vincent Procaccio Dominique Bonneau Patrizia Amati-Bonneau Pascal Reynier Dimitri Krainc Guy Lenaers |
spellingShingle |
Majida Charif Yvette C. Wong Soojin Kim Agnès Guichet Catherine Vignal Xavier Zanlonghi Philippe Bensaid Vincent Procaccio Dominique Bonneau Patrizia Amati-Bonneau Pascal Reynier Dimitri Krainc Guy Lenaers Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy Molecular Neurodegeneration Mitochondria dynamics Mitochondrial disease MIEF1 Mid51 Dominant optic atrophy (DOA) Inherited optic neuropathy (ION) |
author_facet |
Majida Charif Yvette C. Wong Soojin Kim Agnès Guichet Catherine Vignal Xavier Zanlonghi Philippe Bensaid Vincent Procaccio Dominique Bonneau Patrizia Amati-Bonneau Pascal Reynier Dimitri Krainc Guy Lenaers |
author_sort |
Majida Charif |
title |
Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy |
title_short |
Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy |
title_full |
Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy |
title_fullStr |
Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy |
title_full_unstemmed |
Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy |
title_sort |
dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2021-02-01 |
description |
Abstract Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration. |
topic |
Mitochondria dynamics Mitochondrial disease MIEF1 Mid51 Dominant optic atrophy (DOA) Inherited optic neuropathy (ION) |
url |
https://doi.org/10.1186/s13024-021-00431-w |
work_keys_str_mv |
AT majidacharif dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT yvettecwong dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT soojinkim dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT agnesguichet dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT catherinevignal dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT xavierzanlonghi dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT philippebensaid dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT vincentprocaccio dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT dominiquebonneau dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT patriziaamatibonneau dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT pascalreynier dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT dimitrikrainc dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy AT guylenaers dominantmutationsinmief1affectmitochondrialdynamicsandcauseasingularlateonsetopticneuropathy |
_version_ |
1724225014680518656 |