Loss of functional OPA1 unbalances redox state: implications in dominant optic atrophy pathogenesis
Identifieur interne : 001A94 ( Ncbi/Checkpoint ); précédent : 001A93; suivant : 001A95Loss of functional OPA1 unbalances redox state: implications in dominant optic atrophy pathogenesis
Auteurs : Aurélie M. C. Millet ; Ambre M. Bertholet ; Marlène Daloyau ; Pascal Reynier ; Anne Galinier ; Anne Devin ; Bernd Wissinguer ; Pascale Belenguer ; Noélie DavezacSource :
- Annals of Clinical and Translational Neurology [ 2328-9503 ] ; 2016.
Abstract
Mitochondrial respiration, reactive oxygen species levels, antioxidant defenses, and cell death were characterized by biochemical and in situ approaches in both in vitro and in vivo models of
A decrease in aconitase activity suggesting an increase in reactive oxygene species and an induction of antioxidant defenses was observed in cortices of a murine model as well as in
Our study suggests that the pro‐oxidative state induced by
Url:
DOI: 10.1002/acn3.305
PubMed: 27547769
PubMed Central: 4891995
Affiliations:
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1 unbalances redox state: implications in dominant optic atrophy pathogenesis</title>
<author><name sortKey="Millet, Aurelie M C" sort="Millet, Aurelie M C" uniqKey="Millet A" first="Aurélie M. C." last="Millet">Aurélie M. C. Millet</name>
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<author><name sortKey="Bertholet, Ambre M" sort="Bertholet, Ambre M" uniqKey="Bertholet A" first="Ambre M." last="Bertholet">Ambre M. Bertholet</name>
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<author><name sortKey="Daloyau, Marlene" sort="Daloyau, Marlene" uniqKey="Daloyau M" first="Marlène" last="Daloyau">Marlène Daloyau</name>
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<author><name sortKey="Reynier, Pascal" sort="Reynier, Pascal" uniqKey="Reynier P" first="Pascal" last="Reynier">Pascal Reynier</name>
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<author><name sortKey="Galinier, Anne" sort="Galinier, Anne" uniqKey="Galinier A" first="Anne" last="Galinier">Anne Galinier</name>
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<author><name sortKey="Devin, Anne" sort="Devin, Anne" uniqKey="Devin A" first="Anne" last="Devin">Anne Devin</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Loss of functional <styled-content style="fixed-case">OPA</styled-content>
1 unbalances redox state: implications in dominant optic atrophy pathogenesis</title>
<author><name sortKey="Millet, Aurelie M C" sort="Millet, Aurelie M C" uniqKey="Millet A" first="Aurélie M. C." last="Millet">Aurélie M. C. Millet</name>
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<author><name sortKey="Bertholet, Ambre M" sort="Bertholet, Ambre M" uniqKey="Bertholet A" first="Ambre M." last="Bertholet">Ambre M. Bertholet</name>
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</affiliation>
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<author><name sortKey="Daloyau, Marlene" sort="Daloyau, Marlene" uniqKey="Daloyau M" first="Marlène" last="Daloyau">Marlène Daloyau</name>
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</affiliation>
</author>
<author><name sortKey="Reynier, Pascal" sort="Reynier, Pascal" uniqKey="Reynier P" first="Pascal" last="Reynier">Pascal Reynier</name>
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<author><name sortKey="Galinier, Anne" sort="Galinier, Anne" uniqKey="Galinier A" first="Anne" last="Galinier">Anne Galinier</name>
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<author><name sortKey="Devin, Anne" sort="Devin, Anne" uniqKey="Devin A" first="Anne" last="Devin">Anne Devin</name>
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<author><name sortKey="Wissinguer, Bernd" sort="Wissinguer, Bernd" uniqKey="Wissinguer B" first="Bernd" last="Wissinguer">Bernd Wissinguer</name>
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</affiliation>
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<author><name sortKey="Belenguer, Pascale" sort="Belenguer, Pascale" uniqKey="Belenguer P" first="Pascale" last="Belenguer">Pascale Belenguer</name>
<affiliation><nlm:aff id="acn3305-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Davezac, Noelie" sort="Davezac, Noelie" uniqKey="Davezac N" first="Noélie" last="Davezac">Noélie Davezac</name>
<affiliation><nlm:aff id="acn3305-aff-0001"></nlm:aff>
</affiliation>
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<series><title level="j">Annals of Clinical and Translational Neurology</title>
<idno type="eISSN">2328-9503</idno>
<imprint><date when="2016">2016</date>
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<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<sec id="acn3305-sec-0001"><title>Objective</title>
<p><italic><styled-content style="fixed-case">OPA</styled-content>
1</italic>
mutations cause protein haploinsufficiency leading to dominant optic atrophy (<styled-content style="fixed-case">DOA</styled-content>
), an incurable retinopathy with variable severity. Up to 20% of patients also develop extraocular neurological complications. The mechanisms that cause this optic atrophy or its syndromic forms are still unknown. After identifying oxidative stress in a mouse model of the pathology, we sought to determine the consequences of <styled-content style="fixed-case">OPA</styled-content>
1 dysfunction on redox homeostasis.</p>
</sec>
<sec id="acn3305-sec-0002"><title>Methods</title>
<p>Mitochondrial respiration, reactive oxygen species levels, antioxidant defenses, and cell death were characterized by biochemical and in situ approaches in both in vitro and in vivo models of <styled-content style="fixed-case">OPA</styled-content>
1 haploinsufficiency.</p>
</sec>
<sec id="acn3305-sec-0003"><title>Results</title>
<p>A decrease in aconitase activity suggesting an increase in reactive oxygene species and an induction of antioxidant defenses was observed in cortices of a murine model as well as in <styled-content style="fixed-case">OPA</styled-content>
1 downregulated cortical neurons. This increase is associated with a decline in mitochondrial respiration in vitro. Upon exogenous oxidative stress, <styled-content style="fixed-case">OPA</styled-content>
1‐depleted neurons did not further exhibit upregulated antioxidant defenses but were more sensitive to cell death. Finally, low levels of antioxidant enzymes were found in fibroblasts from patients supporting their role as modifier factors.</p>
</sec>
<sec id="acn3305-sec-0004"><title>Interpretation</title>
<p>Our study suggests that the pro‐oxidative state induced by <styled-content style="fixed-case">OPA</styled-content>
1 loss may contribute to <styled-content style="fixed-case">DOA</styled-content>
pathogenesis and that differences in antioxidant defenses can explain the variability in expressivity. Furthermore, antioxidants may be used as therapy as they could prevent or delay DOA symptoms in patients.</p>
</sec>
</div>
</front>
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<tree><noCountry><name sortKey="Belenguer, Pascale" sort="Belenguer, Pascale" uniqKey="Belenguer P" first="Pascale" last="Belenguer">Pascale Belenguer</name>
<name sortKey="Bertholet, Ambre M" sort="Bertholet, Ambre M" uniqKey="Bertholet A" first="Ambre M." last="Bertholet">Ambre M. Bertholet</name>
<name sortKey="Daloyau, Marlene" sort="Daloyau, Marlene" uniqKey="Daloyau M" first="Marlène" last="Daloyau">Marlène Daloyau</name>
<name sortKey="Davezac, Noelie" sort="Davezac, Noelie" uniqKey="Davezac N" first="Noélie" last="Davezac">Noélie Davezac</name>
<name sortKey="Devin, Anne" sort="Devin, Anne" uniqKey="Devin A" first="Anne" last="Devin">Anne Devin</name>
<name sortKey="Galinier, Anne" sort="Galinier, Anne" uniqKey="Galinier A" first="Anne" last="Galinier">Anne Galinier</name>
<name sortKey="Millet, Aurelie M C" sort="Millet, Aurelie M C" uniqKey="Millet A" first="Aurélie M. C." last="Millet">Aurélie M. C. Millet</name>
<name sortKey="Reynier, Pascal" sort="Reynier, Pascal" uniqKey="Reynier P" first="Pascal" last="Reynier">Pascal Reynier</name>
<name sortKey="Wissinguer, Bernd" sort="Wissinguer, Bernd" uniqKey="Wissinguer B" first="Bernd" last="Wissinguer">Bernd Wissinguer</name>
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