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

Molecular Neurodegeneration

Philippe Bensaid¹  Xavier Zanlonghi²  Soojin Kim³  Dimitri Krainc³  Yvette C. Wong³  Agnès Guichet⁴  Catherine Vignal⁵  Guy Lenaers⁶  Dominique Bonneau⁷  Pascal Reynier⁷  Patrizia Amati-Bonneau⁷  Vincent Procaccio⁷  Majida Charif⁸ 

[1] Cabinet d’Ophtalmologie, Morlaix, France;Centre de Compétence Maladies Rares, Clinique Pluridisciplinaire Jules Verne, Nantes, France;Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;Departments of Biochemistry and Genetics, University Hospital Angers, Angers, France;Neuroophthalmology Department, Rothschild Ophthalmologic Foundation, Paris, France;Université d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVasc, Angers, France;Université d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVasc, Angers, France;Departments of Biochemistry and Genetics, University Hospital Angers, Angers, France;Université d’Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVasc, Angers, France;Genetics and Immuno-Cell Therapy Team, Mohammed First University, Oujda, Morocco;

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

DOI  :  10.1186/s13024-021-00431-w

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY