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. 2021 Feb 25;16(1):12.
doi: 10.1186/s13024-021-00431-w.

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

Majida Charif #  1   2 , Yvette C Wong #  3 , Soojin Kim  3 , Agnès Guichet  4 , Catherine Vignal  5 , Xavier Zanlonghi  6 , Philippe Bensaid  7 , Vincent Procaccio  1   4 , Dominique Bonneau  1   4 , Patrizia Amati-Bonneau  1   4 , Pascal Reynier  1   4 , Dimitri Krainc  3 , Guy Lenaers  8
Affiliations

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

Majida Charif et al. Mol Neurodegener. .

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.

Keywords: Dominant optic atrophy (DOA); Inherited optic neuropathy (ION); MIEF1; Mid51; Mitochondria dynamics; Mitochondrial disease; Neurodegeneration; Peripheral visual field.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Characterization of inherited optic neuropathy patients with dominant MIEF1 mutations. a Eye fundus of the right (RE) and left (LE) eye exhibiting severe optic disk pallor in MIEF1 individuals with inherited optic neuropathy (Patient 1 (left 2 panels); Patient 2 (right 2 panels)). b Evaluation of the visual fields revealed peripheral visual field defects in MIEF1 individuals with inherited optic neuropathy (Patient 1 (left 2 panels); Patient 2 (right 2 panels)). c Optical coherence tomography (OCT) recordings of the retinal nerve fiber layer (RNFL) at the papilla of the right (RE, left panel) and left (LE, right panel) eye from Patient 2 with inherited optic neuropathy
Fig. 2
Fig. 2
Genotype of dominant MIEF1 variants in individuals with inherited optic neuropathy. a Genetic analysis identified dominant MIEF1 mutations: heterozygous mutation c.718 T > A in exon 6 of MIEF1 localized at position 240 of the MID51 protein, leading to an amino acid exchange of tyrosine to asparagine (p.Y240N; Patient 1); and heterozygous mutation c.436C > T in exon 5 of MIEF1 localized at position 416 of the MID51 protein, leading to an amino acid exchange of arginine to tryptophan (p.R146W; Patient 2). Additional variant characterization according to the Sift, PolyPhen-2 and Mutation Taster scores are shown. b Alignment of MID51 (NM_019008.5) and MID49 (NM_139162.4) protein sequences around the mutated amino acids (p.R146W (green) and p.Y240N (red)) showing conservation of R146 in MID51. c Localization of the amino acid changes (p.R146W (green) and p.Y240N (red)) on the MID51 protein. MID51 contains a transmembrane domain (TM) mediating its insertion into the outer mitochondrial membrane, and a DRP1 binding region in which Y240 is located
Fig. 3
Fig. 3
Inherited optic neuropathy MIEF1 mutations do not disrupt MID51 localization or oligomerization, but preferentially affect its ability to regulate mitochondrial network dynamics. a and b Representative live-cell confocal images and quantification of mCherry-tagged MID51 (WT; p.Y240N; p.R146W) showing MID51 localization to mitochondria (mEmerald-Mito). (n = 100 cells from 3 experiments/ per condition). Scale bar, 10 μm (inset, 1 μm). c-i Representative immunoblot (α-myc) and quantification of MID51 oligomerization into dimer, tetramer, or high molecular weight (HMW) species from IP (myc) of myc-tagged MID51 (WT; p.Y240N; p.R146W) and control (−-). Mutants MID51 p.Y240N (d-f) and MID51 p.R146W (g-i) show similar oligomerization compared to wild-type MID51 (WT). (n = 3 experiments/per condition). j-m Representative confocal live-cell images and traces (j and k) and analysis (l and m) of mito-PAGFP fluorescence intensity in distal region (10 μm from the site of mitochondrial photoactivation) in high spatial and temporal resolution confocal microscopy live imaging studies, showing increased mitochondrial fusion (white arrows) in wild-type MID51 (WT) condition which is not observed in mutant MID51 p.Y240N and p.R146W conditions. (n = 8 cells (control); n = 9 cells (WT); n = 16 cells (p.Y240N); n = 30 cells (p.R146W), from 3 experiments/per condition). Scale bar, 5 μm. Data are means ± s.e.m. (N.S. = not significant; **P < 0.01; ***P < 0.001; unpaired two-tailed t test (d-i); ANOVA with Tukey’s post-hoc test (b, l, m))
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