Mitochondria and NDD

Mutations in genes encoding mitochondrial proteins lead to primary mitochondrial disorders, which represent one of the most common and debilitating inherited metabolic diseases often resulting in early mortality. Patients with mitochondrial diseases suffer from multi-systemic symptoms, especially affecting organs with high energetic demands such as the brain, muscle, heart, retina, optic nerve, and liver. There is no cure or approved therapy currently available for mitochondrial diseases, certainly due to the complexity of phenotypes associated with mitochondrial dysfunction. Moreover, over the past decades, an emerging role for mitochondrial dysfunction and altered energy metabolism has been associated to the pathogenesis of neurodevelopmental and neurodegenerative disorders. This can be explained by the high energy requirements of neurons and their inability to produce sufficient ATP by glycolysis, resulting in their dependence on functional mitochondria for their integrity.
Our research project aims at improving life conditions of patients suffering from neurological diseases by preserving mitochondrial homeostasis by implementing a treatment, via gene therapy, which effectively and durably preserves the functional integrity of mitochondria within neurons.
The gene therapy candidate chosen is the Neuroglobin because we have already demonstrated its capacity to protect the optic nerve and the cerebellum of the Harlequin mice, which faithfully recapitulates Human mitochondrial diseases.
The neuroglobin was identified, in 2000, as a member of the globin superfamily which is highly conserved throughout evolution and possesses neuroprotective properties. We were involved in demonstrating its localization inside the mitochondria of rodent neurons and its ability to protect respiratory chain function.
To consolidate the proof-of-concept that neuroglobin gene overexpression is beneficial not only for mitochondrial diseases but also for neurological disorders in which symptoms aggravate consecutive to mitochondrial damage we are studying the cerebellum and cerebellar ataxia not due to mitochondrial gene mutations, the Atxn1154Q/2Q mice.
If this treatment effectively and permanently preserves mitochondrial homeostasis of cerebellar neurons in Atxn1154Q/2Q mice, we will strengthen our hypothesis and open the way to design a clinical study involving the neuroglobin.

Members
Edward Ratcliffe (PhD fellow)
Djmila Mouri (PhD fellow)
Dr. Isabel Torres-Cuevas (15%)
Ivan-Millan (Post-doc fellow, 50%)
Marisol Corral-Debrnski (Director of Research CNRS)

Recent Publications
1. H. Cwerman-Thibault, V. Malko-Baverel, G. Le Guilloux, I. Torres-Cuevas, E. Ratcliffe, D. Mouri, V. Mignon, B. Saubaméa, O. Boespflug-Tanguy, P. Gressens, M. Corral-Debrinski. Biochim Biophys Acta Mol Basis Dis (2024) 17:167272. DOI: 10.1016/j.bbadis.2024.167272.
2. H. Cwerman-Thibault, V. Malko-Baverel, G. Le Guilloux, E. Ratcliffe, D. Mouri, I. Torres-Cuevas, I. Millán, B. Saubaméa, V. Mignon, O. Boespflug-Tanguy, Pierre Gressens, Marisol Corral-Debrinski. Mol Ther. 2024: S1525-0016(24)00332-0. DOI: 10.1016/j.ymthe.2024.05.030.
3. H. Cwerman-Thibault, C. Lechauve, V. Malko-Baverel, S. Augustin, G. Le Guilloux, É. Reboussin, J. Degardin-Chicaud, M. Simonutti, T. Debeir, M. Corral-Debrinski. Neurobiol Dis. (2021) 159: 105483. DOI: 10.1016/j.nbd.2021.105483.

Collaborations
Dr. Isabel Torres-Cuevas: Neonatal Research Group of the Health Research Institute La Fe (Valencia, Spain)
Dr. Bruno Saubamea: the Université de Paris, UMR-S 1144 Inserm, Platform of Cellular and Molecular Imaging (Paris)
Dr. Consuelo Chafer-Pericas: Research Group in Alzheimer Disease, Health Research Institute La Fe (Valencia, Spain)

Funding
AFM-Telethon as a strategic project (NEUROGLOBIN & NEUROPROTECTION)
Intellectual Property
PCT/EP2023/068369 / WO2024008709: Intravenous administration of neuroglobin for treating neurological disorders.