Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy

Emmanuelle Sarzi; Marie Seveno; Claire Angebault; Dan Milea; Cecilia Rönnbäck; Melanie Quilès; Mathias Adrian; Joanna Grenier; Angélique Caignard; Annie Lacroux; Christian Lavergne; Pascal Reynier; Michael Larsen; Christian P Hamel; Guy Lenaers; Agnès Müller

doi:10.1093/hmg/ddw117

Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy

Emmanuelle Sarzi, Marie Seveno, Claire Angebault, Dan Milea, Cecilia Rönnbäck, Melanie Quilès, Mathias Adrian, Joanna Grenier, Angélique Caignard, Annie Lacroux, Christian Lavergne, Pascal Reynier, Michael Larsen, Christian P Hamel, Guy Lenaers, Agnès Müller

Department of Clinical Medicine

11 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Human Molecular Genetics
Volume	25
Issue number	12
Pages (from-to)	2539-2551
Number of pages	13
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddw117
Publication status	Published - 15 Jun 2016

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Sarzi, E., Seveno, M., Angebault, C., Milea, D., Rönnbäck, C., Quilès, M., Adrian, M., Grenier, J., Caignard, A., Lacroux, A., Lavergne, C., Reynier, P., Larsen, M., Hamel, C. P., Lenaers, G., & Müller, A. (2016). Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy. Human Molecular Genetics, 25(12), 2539-2551. https://doi.org/10.1093/hmg/ddw117

Sarzi, E, Seveno, M, Angebault, C, Milea, D, Rönnbäck, C, Quilès, M, Adrian, M, Grenier, J, Caignard, A, Lacroux, A, Lavergne, C, Reynier, P, Larsen, M, Hamel, CP, Lenaers, G & Müller, A 2016, 'Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy', Human Molecular Genetics, vol. 25, no. 12, pp. 2539-2551. https://doi.org/10.1093/hmg/ddw117

@article{64eade474a2e40959d6d6242cc2fbbe3,

title = "Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy",

abstract = "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 M{\"u}ller glial cells, responsible for RGC degeneration.",

author = "Emmanuelle Sarzi and Marie Seveno and Claire Angebault and Dan Milea and Cecilia R{\"o}nnb{\"a}ck and Melanie Quil{\`e}s and Mathias Adrian and Joanna Grenier and Ang{\'e}lique Caignard and Annie Lacroux and Christian Lavergne and Pascal Reynier and Michael Larsen and Hamel, {Christian P} and Guy Lenaers and Agn{\`e}s M{\"u}ller",

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doi = "10.1093/hmg/ddw117",

language = "English",

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T1 - Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy

AU - Sarzi, Emmanuelle

AU - Seveno, Marie

AU - Angebault, Claire

AU - Milea, Dan

AU - Rönnbäck, Cecilia

AU - Quilès, Melanie

AU - Adrian, Mathias

AU - Grenier, Joanna

AU - Caignard, Angélique

AU - Lacroux, Annie

AU - Lavergne, Christian

AU - Reynier, Pascal

AU - Larsen, Michael

AU - Hamel, Christian P

AU - Lenaers, Guy

AU - Müller, Agnès

PY - 2016/6/15

Y1 - 2016/6/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddw117

DO - 10.1093/hmg/ddw117

M3 - Journal article

C2 - 27260406

SN - 0964-6906

VL - 25

SP - 2539

EP - 2551

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 12

ER -

Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy

Abstract

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