Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy.
OPA1 mutations are responsible for autosomal dominant optic atrophy (ADOA), a progressive blinding disease characterized by retinal ganglion cell (RGC) degeneration and large phenotypic variations, the underlying mechanisms of which are poorly understood. OPA1 encodes a mitochondrial protein with essential biological functions, its main roles residing in the control of mitochondrial membrane dynamics as a pro-fusion protein and prevention of apoptosis. Considering recent findings showing the importance of the mitochondrial fusion process and the involvement of OPA1 in controlling steroidogenesis, we tested the hypothesis of deregulated steroid production in retina due to a disease-causing OPA1 mutation and its contribution to the visual phenotypic variations. Using the mouse model carrying the human recurrent OPA1 mutation, we disclosed that Opa1 haploinsufficiency leads to very high circulating levels of steroid precursor pregnenolone in females, causing an early-onset vision loss, abolished by ovariectomy. In addition, steroid production in retina is also increased which, in conjunction with high circulating levels, impairs estrogen receptor expression and mitochondrial respiratory complex IV activity, promoting RGC apoptosis in females. We further demonstrate the involvement of Muller glial cells as increased pregnenolone production in female cells is noxious and compromises their role in supporting RGC survival. In parallel, we analyzed ophthalmological data of a multicentre OPA1 patient cohort and found that women undergo more severe visual loss at adolescence and greater progressive thinning of the retinal nerve fibres than males. Thus, we disclosed a gender-dependent effect on ADOA severity, involving for the first time steroids and Müller glial cells, responsible for RGC degeneration.
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France, emmanuelle.sarzi@inserm.fr.
Emmanuelle
E
Sarzi
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.
Marie
M
Seveno
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.
Claire
C
Angebault
Département de Biochimie et Génétique, UMR CNRS 6214-INSERM 1083, Centre Hospitalier Universitaire, Angers, France.|Singapore National Eye Centre, Singapore.|Singapore Eye Research Institute, Singapore.|Duke-NUS, Singapore.
Dan
D
Milea
Department of Ophthalmology, Glostrup Hospital, Glostrup, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Cecilia
C
Rönnbäck
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier - Faculté de Pharmacie-Montpellier, France.
Melanie
M
Quilès
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.
Mathias
M
Adrian
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.|Centre de référence des affections sensorielles d'origine génétique, Hôpital Gui de Chauliac, Montpellier, France.
Joanna
J
Grenier
Département de Biochimie et Génétique, UMR CNRS 6214-INSERM 1083, Centre Hospitalier Universitaire, Angers, France.
Angélique
A
Caignard
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.|Centre de référence des affections sensorielles d'origine génétique, Hôpital Gui de Chauliac, Montpellier, France.
Annie
A
Lacroux
Institut Montpelliérain Alexander Grothendieck. Université Montpellier 3, France and.
Christian
C
Lavergne
Département de Biochimie et Génétique, UMR CNRS 6214-INSERM 1083, Centre Hospitalier Universitaire, Angers, France.
Pascal
P
Reynier
Department of Ophthalmology, Glostrup Hospital, Glostrup, Denmark.|Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Michael
M
Larsen
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.|Centre de référence des affections sensorielles d'origine génétique, Hôpital Gui de Chauliac, Montpellier, France.
Christian P
CP
Hamel
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France, emmanuelle.sarzi@inserm.fr.
Cécile
C
Delettre
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.|PREMMI, UMR CNRS 6214-INSERM 1083, Université d'Angers, France.
Guy
G
Lenaers
INSERM U1051 - Institut des Neurosciences de Montpellier, Montpellier, France.|Université de Montpellier - Faculté de Pharmacie-Montpellier, France.
Agnès
A
Müller
D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D009900:Optic Nerve / Q000473:pathology; D011284:Pregnenolone / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000473:pathology*; D012727:Sex Characteristics
D050505:Mutant Proteins; D011284:Pregnenolone; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human