Team
Team manager: Belenguer Pascale
A mitochondrial gate to neuronal plasticity and neurodegeneration.
The fine regulation of mitochondrial functions, including energy supply, is vital for highly specialized and energy-demanding cells, like neurons. Mitochondrial dynamics, which corresponds to fusion and fission of mitochondria, controls their main functions, their adaptability to cellular needs as well as their quality control. Several neurodegenerative diseases are directly associated with mutations in key mitochondrial fusion and fission proteins, such as the fusogenic OPA1 protein, in which mutations cause a dominant form of optic atrophy (DOA). Moreover, alterations of mitochondrial functions (energy, oxidative stress), mitochondrial dynamics and quality control contribute to the etiology of several neurodegenerative diseases, such as Alzheimer’s (AD). Moreover, the main role of mitochondria in neurogenesis has been recently revealed.
Our current projects aim at deciphering the mechanisms underlying the impact of mitochondrial dynamics and quality control on neuronal homeostasis and synaptic plasticity, spanning from adult neurogenesis and related complex brain functions such as memory, to neurodegeneration. Furthermore, we are developing pharmacological treatments and gene therapies in preclinical studies for mitochondria-related neurodegenerations such as DOA and AD.
Embryonic rat cortical neuron after 6 days in vitro. Detection by immuno-fluorescence of the neuronal marker MAP2 (red) and of mitochondria (green and yellow).
Project 1
The impact of visual impairments has risen in our developed countries with the contemporary means of visual communication and an ageing population. Optic nerve atrophies are often due to defects in mitochondria, as Dominant Optic Atrophy (DOA) caused by mutations of the mitochondrial OPA1 protein, involved in mitochondrial dynamics. As there is no treatment for DOA, we are exploring an original therapeutic approach in collaboration with Daniel Dunia (Infinity, Toulouse). We are focusing on a protein, called X, derived from a neurotropic virus, demonstrated by our collaborator’s team to protect neurons against diverse neurodegenerative insults. Interestingly, these effects require X to be located in mitochondria and are correlated with changes in mitochondrial dynamics. We are therefore testing whether X can protect neurons against the consequences of OPA1 deficiencies using both in vitro and in vivo DOA models. We are also developing pre-clinical pharmacological assays using two repurposed drugs, chomiphene and hexestrol, which we have previously identified as compounds capable of compensating mitochondrial defects induced by the loss of OPA1 in yeast.
Team’s members involved in the project: Djamaa Atamena, Marlène Botella and Pascale Belenguer (PI)
Neurons respectively showing filamentous or fragmented mitochondria (green). Treatments with X, clomiphene or hexestrol compensate the alteration in mitochondrial morphology of DOA neurons.
Project 2
In order to study the cellular mechanisms of neurodegeneration in humans during aging or in pathological condition (Dominant Optic Atrophy, Alzheimer’s disease), our project aims to develop models of human neurons in culture. We chose a direct conversion approach from fibroblasts to neurons, allowing to preserve epigenetic and metabolic signatures associated with ageing, unlike the use of reprogrammed stem cells. Establishing such models from patient biopsies will allow us to test and validate the efficacy of treatments aimed at compensating the mitochondrial and neuronal deficits associated with these diseases.
Team’s members involved in the project: P. Belenguer and C. Mollereau (PI)
Directly reprogrammed human neurons at day 35 of culture.
Immunofluorescence detection of the neuronal markers MAP2 (green) and Tau (red).
Project 3
In collaboration with Claire Rampon (Remember, CRCA), this project addresses the little-explored question of the involvement of mitochondria in the generation and maintenance of adult-born neurons.
We have previously demonstrated that mitochondrial defects induced by the inactivation of OPA1 are associated with hippocampal adult neurogenesis and related memory process impairments, and that these defects can be corrected by pharmacological treatment targeting mitochondrial dynamics. Interestingly, we also evidenced that similar alterations of adult neurogenesis and related memory deficits observed in Alzheimer’s disease (AD) are rescued by amplifying mitochondrial density.
We now explore the role of mitophagy, a process that selectively eliminates damaged or supernumerary mitochondria, in hippocampal adult neurogenesis and related memory processes in healthy and AD contexts using in vitro and mouse models.
Team’s members involved in the project: Zahra Ghasemi, Marie-Christine Miquel, Pascale Belenguer and Laetitia Arnauné (PI).
Detection by immuno- fluorescence of mitochondria (red) and autophagosome (green) in cultured neurons. Mitophagy event corresponds to a mitochondrion engulfed in an autophagosome that will fuse with a lysosome leading to degradation of its content.
– Atamena D, Gurram V, Petsophonsakul P, Khosrobakhsh F, Arrázola MS, Botella M, Wissinger B, Szelechowski M, Belenguer P. Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis. Front Mol Neurosci. 2023;16:1241222. doi: 10.3389/fnmol.2023.1241222.
– Andraini T, Moulédous L, Petsophonsakul P, Florian C, Gauzin S, Botella-Daloyau M, Arrázola M, Nikolla K, Philip A, Leydier A, Marque M, Arnauné-Pelloquin L, Belenguer P, Rampon C, Miquel MC. Mitochondrial OPA1 Deficiency Is Associated to Reversible Defects in Spatial Memory Related to Adult Neurogenesis in Mice. eNeuro. 2023;10(11):ENEURO.0073-23.2023. doi: 10.1523/ENEURO.0073-23.2023.
– Millet AMC, Coustham C, Champigny C, Merabet N., Botella M, Demeilliers C, Devin A, Galinier A, Belenguer P, Bordeneuve-Guibé J, Davezac N. OPA1 deficiency impairs oxidative metabolism in cycling cells, underlining a translational approach for degenerative diseases. Dis Model Mech. 2023;16(9):dmm050266. doi: 10.1242/dmm.050266.
– -Arrázola MS, Andraini T, Szelechowski M, Mouledous L, Arnauné-Pelloquin L, Davezac N, Belenguer P, Rampon C, Miquel MC Mitochondria in Developmental and Adult Neurogenesis. Neurotox Res, 2019; 36(2):257-267. doi: 10.1007/s12640-018-9942-y. Review
– Chao de la Barca JM, Arrázola MS, Bocca C, Arnauné-Pelloquin L, Olga Iuliano,Tcherkez G, Lenaers G, Simard G, Belenguer P*, Reynier P*. () The metabolomic signature of Opa1 deficiency in rat primary cortical neurons shows aspartate/glutamate deficiency and phospholipids remodeling. Scientific Report 2019; 9(1):610. doi: 10.1038/s41598-019-42554-7. * co-last.
– Richetin K, Moulis M, Millet A, Arràzola MS, Andraini T, Hua J, Davezac N, Roybon L, Belenguer P, Miquel* MC, Rampon* C. Amplifying mitochondrial function rescues adult neurogenesis in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2017 102:113-124. doi: 10.1016/j.nbd.2017.03.002. * co-last.
– Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Arnauné-Pelloquin L, Davezac N, Mils V, Miquel MC, Rojo M, Belenguer P. (2016). Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis. 2017; 90:3-19. doi: 10.1016/j.nbd.2015.10.011. Review
– Moulis MF, Millet AM, Daloyau M, Miquel MC, Ronsin B, Wissinger B, Arnauné-Pelloquin L, Belenguer P. OPA1 haploinsufficiency induces a BNIP3-dependent decrease in mitophagy in neurons: relevance to Dominant Optic Atrophy. J Neurochem. 2017 140(3):485-494. doi: 10.1111/jnc.13894.
– Bertholet AM, Millet A, Guillermin O, Daloyau M, Davezac N, Miquel MC and Belenguer P. OPA1 loss affects neuronal maturation Brain 2013 136(Pt 5):1518-33. doi: 10.1093/brain/awt060.
Financements
Affiliation
