Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy

Majida Charif,Yvette C Wong,Patrizia Amati-Bonneau,Xavier Zanlonghi,Vincent Procaccio,Dimitri Krainc,Pascal Reynier,Guy Lenaers,Soojin Kim,Philippe Bensaid,Agnès Guichet,Dominique Bonneau,Catherine Vignal

doi:10.1186/s13024-021-00431-w

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.

Highlights

Inherited Optic Neuropathies (ION) are the most common mitochondrial diseases, leading to the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss [1, 2]
We and others described cohorts of individuals affected by Dominant optic atrophy (DOA) caused either by mutations in Spastic paraplegia 7 (SPG7) (MIM#602783) or in AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) (MIM#604581) [11,12,13], two genes encoding mAAA-proteases acting on mitochondrial fusion through the indirect control of Optic Atrophy Protein 1 (OPA1) processing, and involved in recessive hereditary spastic paraplegia type 7 [14] and dominant spinocerebellar ataxia 28 [15], respectively
DNM1L encodes DRP1, another dynamin-related GTPase which requires a set of adaptor proteins including Mitochondrial dynamics protein 51 (MID51), Mitochondrial dynamics protein 49 (MID49), and Mitochondrial fission factor (MFF) to be recruited on the mitochondrial outer membrane to exert and regulate its pro-fission activity [18,19,20]

Summary

Introduction

Inherited Optic Neuropathies (ION) are the most common mitochondrial diseases, leading to the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss [1, 2]. We and others described cohorts of individuals affected by DOA caused either by mutations in SPG7 (MIM#602783) or in AFG3L2 (MIM#604581) [11,12,13], two genes encoding mAAA-proteases acting on mitochondrial fusion through the indirect control of OPA1 processing, and involved in recessive hereditary spastic paraplegia type 7 [14] and dominant spinocerebellar ataxia 28 [15], respectively.

Results

Conclusion