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Neurological Diseases Associated with Mutations in the Mitochondrial Fusion Machinery

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Abstract

Dominant optic atrophy (DOA) and Charcot-Marie-Tooth type 2A disease (CMT2A) are inherited neurological disorders primarily affecting retinal ganglion cells and peripheral nerves, and secondarily, other neuronal cells with high energetic requirements. The discovery of OPA1 mutations in DOA patients and MFN2 ­mutations in CMT2A patients, has defined a new subset of mitochondrial diseases related to mitochondrial dynamics. OPA1 and MFN2 are both dynamin GTPases that promote the fusion of the mitochondrial network. Since diseases related to OPA1 and MFN2 mutations show some clinical similarities, their pathophysiological mechanisms are believed to share some common mitochondrial dysfunctions. These mechanisms are closely ­interdependent and involve mitochondrial fusion, motility along the axons, energy ­production and metabolism, maintenance of the organelle and its genome, as well as ­susceptibility to apoptosis. This chapter presents recent findings on: (1) the clinical diversity of OPA1- and MFN2-related diseases; (2) the spectrum of mutations in the OPA1 and MFN2 genes and their consequences at the protein level; and (3) the pathophysiology of DOA and CMT2A as characterized in cellular and mouse models. Finally, we discuss the therapeutic perspectives opened up by the current knowledge of these diseases.

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Abbreviations

aa:

amino acid

ADP:

adenosine-5’-diphosphate

ANT:

adenine nucleotide translocator

ATP:

adenosine-5’-triphosphate

CMT disease:

Charcot-Marie-Tooth disease

CPEO:

chronic progressive external ophthalmoplegia

DOA:

dominant optic atrophy

DRG:

dorsal root ganglion

ENU:

N-ethyl-N-nitrosurea

GTP:

guanosine triphosphate

GTPase:

guanosine triphosphate phosphorylase

HR:

heptad repeat domain

IMM:

inner mitochondrial membrane.

LHON:

Leber’s hereditary optic neuropathy

MEF:

mouse embryonic fibroblasts

MFN2:

Mitofusin 2

mtDNA:

mitochondrial DNA

OMA1:

overlapping activity with M-AAA protease 1

OMM:

outer mitochondrial membrane

OPA1:

optic atrophy 1

OXPHOS:

oxidative phosphorylation

Phb1/2:

prohibitins 1 and 2

RGC:

retinal ganglion cell

TM:

transmembrane domain

VEP:

visual evoked potential

YME1L:

YME1-like protein 1

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Acknowledgements

We are grateful to Kanaya Malkani for critical reading and comments on the manuscript. Our work is supported by INSERM, the University Hospital of Angers (PHRC 04–12), the University of Angers, France; and by grants from the following patients’ associations: “Association contre les Maladies Mitochondriales (AMMi)”, “Ouvrir les Yeux (OLY)”, “Retina France” and “Union Nationale des Aveugles et Déficients Visuels (UNADEV)”.

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  1. Inserm U1051, Institut des Neurosciences de Montpellier, Universités de Montpellier I et II, Montpellier, France

    Guy Lenaers, Cécile Delettre, Emmanuelle Sarzi & Christian Hamel

  2. UMR CNRS 6214 - Inserm U771, Angers, France

    Dominique Bonneau, Patrizia Amati-Bonneau, Dan Miléa, Christophe Verny, Vincent Procaccio & Pascal Reynier

  3. Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France

    Dominique Bonneau, Patrizia Amati-Bonneau, Vincent Procaccio & Pascal Reynier

  4. Département d’Ophtalmologie, Centre Hospitalier Universitaire, Angers, France

    Dan Miléa

  5. Département de Neurologie, Centre Hospitalier Universitaire, Angers, France

    Christophe Verny

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    Bingwei Lu

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Lenaers, G. et al. (2011). Neurological Diseases Associated with Mutations in the Mitochondrial Fusion Machinery. In: Lu, B. (eds) Mitochondrial Dynamics and Neurodegeneration. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1291-1_6

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