Publications by authors named "Aurélie Millet"

8 Publications

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The mitochondrial metabolic function of is modulated by .

FASEB J 2019 08 29;33(8):8925-8934. Epub 2019 Apr 29.

Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.

Mitochondrial metabolic plasticity is a key adaptive mechanism in response to changes in cellular metabolic demand. Changes in mitochondrial metabolic efficiency have been linked to pathophysiological conditions, including cancer, neurodegeneration, and obesity. The ubiquitously expressed (Parkinsonism-associated deglycase) is known as a Parkinson's disease gene and an oncogene. The pleiotropic functions of include reactive oxygen species scavenging, RNA binding, chaperone activity, endocytosis, and modulation of major signaling pathways involved in cell survival and metabolism. Nevertheless, how these functions are linked to the role of in mitochondrial plasticity is not fully understood. In this study, we describe an interaction between and that regulates the localization of , in a hypoxia-dependent manner, either to the cytosol or to mitochondria. This interaction acts as a modulator of mitochondrial metabolic efficiency and a switch between glycolysis and oxidative phosphorylation. Modulation of this novel molecular mechanism of mitochondrial metabolic efficiency is potentially involved in the neuroprotective function of as well as its role in proliferation of cancer cells.-Weinert, M., Millet, A., Jonas, E. A., Alavian, K. N. The mitochondrial metabolic function of is modulated by .
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http://dx.doi.org/10.1096/fj.201802754RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988861PMC
August 2019

Amplifying mitochondrial function rescues adult neurogenesis in a mouse model of Alzheimer's disease.

Neurobiol Dis 2017 Jun 10;102:113-124. Epub 2017 Mar 10.

Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France. Electronic address:

Adult hippocampal neurogenesis is strongly impaired in Alzheimer's disease (AD). In several mouse models of AD, it was shown that adult-born neurons exhibit reduced survival and altered synaptic integration due to a severe lack of dendritic spines. In the present work, using the APPxPS1 mouse model of AD, we reveal that this reduced number of spines is concomitant of a marked deficit in their neuronal mitochondrial content. Remarkably, we show that targeting the overexpression of the pro-neural transcription factor Neurod1 into APPxPS1 adult-born neurons restores not only their dendritic spine density, but also their mitochondrial content and the proportion of spines associated with mitochondria. Using primary neurons, a bona fide model of neuronal maturation, we identified that increases of mitochondrial respiration accompany the stimulating effect of Neurod1 overexpression on dendritic growth and spine formation. Reciprocally, pharmacologically impairing mitochondria prevented Neurod1-dependent trophic effects. Thus, since overexpression of Neurod1 into new neurons of APPxPS1 mice rescues spatial memory, our present data suggest that manipulating the mitochondrial system of adult-born hippocampal neurons provides neuronal plasticity to the AD brain. These findings open new avenues for far-reaching therapeutic implications towards neurodegenerative diseases associated with cognitive impairment.
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http://dx.doi.org/10.1016/j.nbd.2017.03.002DOI Listing
June 2017

Lebecetin, a C-type lectin, inhibits choroidal and retinal neovascularization.

FASEB J 2017 03 14;31(3):1107-1119. Epub 2016 Dec 14.

Sorbonne Universités, Université Pierre et Marie Curie, INSERM, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France;

Angiogenesis is a cause of visual impairment and blindness in the wet form of age-related macular degeneration and in ischemic retinopathies. Current therapies include use of anti-VEGF agents to reduce choroidal neovascularization (CNV) and edema. These treatments are effective in most cases, but spontaneous or acquired resistance to anti-VEGF and possible adverse effects of long-term VEGF inhibition in the retina and choroid highlight a need for additional alternative therapies. Integrins αvβ3 and αvβ5, which regulate endothelial cell proliferation and stabilization, have been implicated in ocular angiogenesis. Lebecetin (LCT) is a 30-kDa heterodimeric C-type lectin that is isolated from venom and interacts with α5β1- and αv-containing integrins. We previously showed that LCT inhibits human brain microvascular endothelial cell adhesion, migration, proliferation, and tubulogenesis. To evaluate the inhibitory effect of LCT on ocular angiogenesis, we cultured aortic and choroidal explants in the presence of LCT and analyzed the effect of LCT on CNV in the mouse CNV model and on retinal neovascularization in the oxygen-induced retinopathy model. Our data demonstrate that a single injection of LCT efficiently reduced CNV and retinal neovascularization in these models.-Montassar, F., Darche, M., Blaizot, A., Augustin, S., Conart, J.-B., Millet, A., Elayeb, M., Sahel, J.-A., Réaux-Le Goazigo, A., Sennlaub, F., Marrakchi, N., Messadi, E., Guillonneau, X. Lebecetin, a C-type lectin, inhibits choroidal and retinal neovascularization.
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http://dx.doi.org/10.1096/fj.201600351RDOI Listing
March 2017

OPA1 haploinsufficiency induces a BNIP3-dependent decrease in mitophagy in neurons: relevance to Dominant Optic Atrophy.

J Neurochem 2017 02 20;140(3):485-494. Epub 2016 Dec 20.

Research Center on Animal Cognition (CRCA), Center for Integrative Biology (CBI), Toulouse University, CNRS, UPS, France.

Dominant optic atrophy (DOA) is because of mutations in the mitochondrial protein OPA1. The disease principally affects retinal ganglion cells, whose axons degenerate leading to vision impairments, and sometimes other neuronal phenotypes. The exact mechanisms underlying DOA pathogenesis are not known. We previously demonstrated that the main role of OPA1, as a mitochondrial fusogenic and anti-apoptotic protein, are inhibited by interaction with the stress inducible pro-apoptotic BNIP3 protein. Because BNIP3 was recently reported to participate in autophagy and mitophagy, we tested the involvement of these processes in DOA pathogenesis. Using an in vitro neuronal model of DOA, we identified a BNIP3 down-regulation that reduced autophagy and mitophagy. Restoring BNIP3 had a biphasic effect, first rescuing autophagy and mitophagy levels but later leading to cell death. Similarly, in an in vivo mouse model of DOA, we showed that BNIP3 levels are decreased in young adult mice and increase to normal levels upon aging, paralleling disease progression. Altogether, our results indicate that the relationship between OPA1 and BNIP3 may have important bearings on DOA pathogenesis.
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http://dx.doi.org/10.1111/jnc.13894DOI Listing
February 2017

Loss of functional OPA1 unbalances redox state: implications in dominant optic atrophy pathogenesis.

Ann Clin Transl Neurol 2016 Jun 25;3(6):408-21. Epub 2016 Apr 25.

Center of Developmental Biology (CBD)/Research Center on Animal Cognition (CRCA) Center for Integrative Biology (CBI) Toulouse University, CNRS, UPS Toulouse France.

Objective: OPA1 mutations cause protein haploinsufficiency leading to dominant optic atrophy (DOA), 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 OPA1 dysfunction on redox homeostasis.

Methods: 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 OPA1 haploinsufficiency.

Results: 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 OPA1 downregulated cortical neurons. This increase is associated with a decline in mitochondrial respiration in vitro. Upon exogenous oxidative stress, OPA1-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.

Interpretation: Our study suggests that the pro-oxidative state induced by OPA1 loss may contribute to DOA 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.
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http://dx.doi.org/10.1002/acn3.305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891995PMC
June 2016

An approach for interlaboratory comparison of conventional and real-time PCR assays for diagnosis of human leishmaniasis.

Exp Parasitol 2013 Jul 3;134(3):281-9. Epub 2013 Apr 3.

WHO Collaborating Center for Leishmaniasis, Servicio de Parasitología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo, Km2, 28220 Madrid, Spain.

Protozoa of the Leishmania genus are transmitted to humans by the bite of infected sandflies, and are the causative agents of leishmaniasis which ranges from cutaneous to visceral clinical forms. The definitive diagnosis of leishmaniasis has relied traditionally on parasite demonstration, either by microscopy or culture; in the last years, diagnosis based on PCR methods has overcome some drawbacks of traditional methods, increasing sensitivity and allowing using less invasive sampling for diagnosis. However, there are not defined protocols and almost each laboratory applies its own in-house method. Although there are several studies comparing the performance of different methods within the same laboratory, those addressing interlaboratory comparison are scarce, in spite of the growing number of collaborative projects between partners from different leishmaniasis endemic and non-endemic countries. In this work we propose a protocol for interlaboratory comparison of conventional and real-time PCR methods involving four participant laboratories from four different endemic regions in four continents; the protocol includes a quality control step and reduces the variability among the samples tested by each participant. A panel of 77 samples from human origin and 9 from different parasite strains was blindly tested by the participants, aiming to assess the sensitivity of the different methods as well as their usefulness for species identification. Real-time PCR methods targeting the kDNA minicircles returned the highest sensitivity, while both PCR targeting ITS-1 and further HaeIII digestion and a combined algorithm including hsp70 PCR and restriction fragment length polymorphism analysis were the most appropriate approaches for species identification.
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http://dx.doi.org/10.1016/j.exppara.2013.03.026DOI Listing
July 2013

OPA1 loss of function affects in vitro neuronal maturation.

Brain 2013 May 29;136(Pt 5):1518-33. Epub 2013 Mar 29.

Universite´ de Toulouse, Centre de Biologie du Développement, CNRS UMR5547/Université Paul Sabatier, Toulouse, France.

Mitochondrial dynamics control the organelle's morphology, with fusion leading to the formation of elongated tubules and fission leading to isolated puncta, as well as mitochondrial functions. Recent reports have shown that disruptions of mitochondrial dynamics contribute to neurodegenerative diseases. Mutations of the inner membrane GTPase OPA1 are responsible for type 1 dominant optic atrophy, by mechanisms not fully understood. We show here that in rodent cortical primary neurons, downregulation of the OPA1 protein leads to fragmented mitochondria that become less abundant along the dendrites. Furthermore, this inhibition results in reduced expression of mitochondrial respiratory complexes as well as mitochondrial DNA, decreased mitochondrial membrane potential, and diminished reactive oxygen species levels. The onset of synaptogenesis was markedly impaired through reductions in pre- and postsynaptic structural protein expression and synapse numbers without first affecting the dendritic arborization. With longer time in culture, OPA1 extinction led to a major restriction of dendritic growth, together with reduction of synaptic proteins. Furthermore, in maturing neurons we observed a transitory increase in mitochondrial filament length, associated with marked changes in the expression levels of OPA1, which occurred at the onset of synaptogenesis simultaneously with transitory increase in reactive oxygen species levels and NRF2/NFE2L2 nuclear translocation. This observation suggests that mitochondrial hyperfilamentation acts upstream of a reactive oxygen species-dependent NRF2 transcriptional activity, possibly impacting neuronal maturation, such a process being impaired by insufficient amount of OPA1. Our findings suggest a new role for OPA1 in synaptic maturation and dendritic growth through maintenance of proper mitochondrial oxidative metabolism and distribution, highlighting the role of mitochondrial dynamics in neuronal functioning and providing insights into dominant optic atrophy pathogenesis, as OPA1 loss affecting neuronal maturation could lead to early synaptic dysfunction.
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http://dx.doi.org/10.1093/brain/awt060DOI Listing
May 2013

Investigating the mechanism of the nucleocapsid protein chaperoning of the second strand transfer during HIV-1 DNA synthesis.

J Mol Biol 2007 Dec 5;374(4):1041-53. Epub 2007 Oct 5.

Photophysique des interactions biomoléculaires, UMR 7175 CNRS, Institut Gilbert Laustriat, Faculté de Pharmacie, Université Louis Pasteur, Strasbourg 1, 74, Route du Rhin, 67401 ILLKIRCH Cedex, France.

Conversion of the human immunodeficiency virus type 1 (HIV-1) genomic RNA into the proviral DNA by reverse transcriptase involves two obligatory strand transfers that are chaperoned by the nucleocapsid protein (NC). The second strand transfer relies on the annealing of the (-) and (+) copies of the primer binding site, (-)PBS and (+) PBS, which fold into complementary stem-loops (SLs) with terminal single-stranded overhangs. To understand how NC chaperones their hybridization, we investigated the annealing kinetics of fluorescently labelled (+)PBS with various (-)PBS derivatives. In the absence of NC, the (+)/(-)PBS annealing was governed by a second-order pathway nucleated mainly by the single-stranded overhangs of the two PBS SLs. The annealing reaction appeared to be rate-limited by the melting of the stable G.C-rich stem subsequent to the formation of the partially annealed intermediate. A second pathway nucleated through the loops could be detected, but was very minor. NC(11-55), which consists primarily of the zinc finger domain, increased the (-)/(+) PBS annealing kinetics by about sixfold, by strongly activating the interaction between the PBS loops. NC(11-55) also activated (-)/(+) PBS annealing through the single-strand overhangs, but by a factor of only 2. Full-length NC(1-55) further increased the (-)/(+)PBS annealing kinetics by tenfold. The NC-promoted (-)/(+)PBS mechanism proved to be similar with extended (-)DNA molecules, suggesting that it is relevant in the context of proviral DNA synthesis. These findings favour the notion that the ubiquitous role of NC in the viral life-cycle probably relies on the ability of NC to chaperone nucleic acid hybridization via different mechanisms.
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http://dx.doi.org/10.1016/j.jmb.2007.10.001DOI Listing
December 2007