Etude des fonctions des Sidéroflexines, une nouvelle famille de protéines mitochondriales

Study of the functions of sideroflexins, a new family of mitochondrial proteins

• Auteur / Autrice : Nesrine Tifoun
• Direction : Nathalie Le Floch, Bernard Mignotte
• Type : Thèse de doctorat
• Discipline(s) : Sciences de la vie et de la santé
• Date : Soutenance le 29/03/2021
• Etablissement(s) : université Paris-Saclay
• Ecole(s) doctorale(s) : École doctorale Structure et dynamique des systèmes vivants (Gif-sur-Yvette, Essonne ; 2015-....)
• Partenaire(s) de recherche : Laboratoire : Laboratoire de génétique et biologie cellulaire (LGBC)
• Partenaire(s) de recherche : référent : Université de Versailles-Saint-Quentin-en-Yvelines (1991-....)
• Jury : Président / Présidente : David Macherel
• Jury : Examinateurs / Examinatrices : Magalie Lecourtois, Stephen Manon, Ioana Ferecatu, Géraldine Liot
• Jury : Rapporteurs / Rapporteuses : Magalie Lecourtois, Stephen Manon

Mots clés

Mots clés contrôlés

Maladies neurodégénératives

Drosophila melanogaster

Protéines mitochondriales

Mots clés libres

Sidéroflexines

Mitochondrie

Apoptose

Drosophila melanogaster

Maladies neurodégénératives

Sideroflexns

Mitochondria

Apoptosis

Drosophila melanogaster

Neurodegenerative diseases

Résumé

Les sidéroflexines forment une famille de transporteurs mitochondriaux encore peu étudiés. Leur forte conservation chez les eucaryotes suggère un rôle important dans la régulation des fonctions mitochondriales, mais ce rôle est encore mal compris. Récemment, il a été montré qu’elles étaient impliquées dans la voie du métabolisme à un carbone et que leur dérégulation impactait l’homéostasie du fer et la respiration mitochondriale. En outre, de smutations de SFXN4 sont responsables d’une maladie mitochondriale rare, le syndrome COXPD18. Pour mieux comprendre les fonctions de SFXN, j’ai développé mes travaux de recherche selon deux axes prioritaires : 1) la recherche de partenaires de SFXN1 en cellules humaines ; 2) l’étude des activités des sidéroflexines de drosophile (dSfxn) vis-à-vis de l’apoptose, processus de mort cellulaire régulé par la mitochondrie.Notre recherche de partenaires physiques de SFXN1 révèle que cette protéine interagit avec des sous-unités de la chaîne respiratoire et les protéines TIM50, HSD10 et ATAD3A. Ces interactions pourraient expliquer les altérations de la respiration mitochondriale observées dans certaines études et permettent d’envisager un rôle des SFXN dans d’autres processus mitochondriaux tels que la synthèse des ARNt mitochondriaux et l’organisation mitochondriale, processus dans lesquels sont impliqués HSD10 et ATAD3A, respectivement.Chez la drosophile, j’ai pu montrer que la modulation des niveaux de dSfxn1/3 et dSfxn2 affectait l’apoptose induite par Rbf1, orthologue de Rb et Debcl, membre pro-apoptotique de la famille Bcl2. Enfin, j’ai généré des résultats suggérant un rôle essentiel de ces protéines dans la régulation de la physiologie neuronale. En effet, la déplétion des dSfxn dans les neurones in vivo chez la drosophile se traduit par une diminution de la longévité des drosophiles et unemodification de leur comportement locomoteur.

Sideroflexins (SFXN) form a new family of mitochondrial proteins. Their functions are currently unknown. These proteins are evolutionary conserved and found from yeast to humans. Five SFXN exist in vertebrates. SFXN1, the first member of the family, was described in flexed-tail mouse that harbors a mutation in the SFXN1 gene. Other members of the sideroflexin family have been described later. Nevertheless since the discovery of SFXN1 few data on the putative functions of the sideroflexins exist. When the key word “sideroflexin” is typed in Pubmed database only thirteen articles are found. Interestingly most recent articles suggest the involvement of sideroflexins in neurodegenerative disorders and mitochondriopathies. We are thus interested in understanding the normal and pathologic functions of sideroflexins at the mitochondrial level. Sideroflexins present five putative transmembrane domains in their structure. These proteins are localized at the inner mitochondrial membrane. A putative function of transporter has been proposed for SFXNs. Fleming and colleagues suggest that SFXN1 was involved in the iron metabolism since flexed-tail mouse displays sideroblastic anemia that is characterized by iron deposition at the mitochondria in erythrocytes. This has not been experimentally proved and another mutation (affecting Madh5 gene) has been later associated with flexed-tail phenotype. SFXN have also been proposed as tricarboxylate transporters. However, their predicted structure is different from that of the other members belonging to the superfamily of anion transporters. Thus the functions of sideroflexins remain largely unknown. Mitochondria occupy a central place in the energetics metabolism and are also involved in various pathologies such as neurodegenerative disorders, cancers and mitochondriopathies. In neurodegenerative diseases such as Parkinson disease (PD), Alzheimer disease (AD) or Huntington disease (HD), defects in mitochondrial dynamics and mitochondrial respiration are observed. Moreover mutant proteins involved in these pathologies accumulate at the mitochondria. Recently involvement of SFXN1 and SFXN3 in AD and PD respectively has been proposed. Furthermore mutations in SFXN4 are thought to be causative of a mitochondriopathy. Defects in mitochondrial respiration are observed consecutive to a loss of function of SFXN4. In the study of Amorim et al, defects in mitochondrial respiration are not seen with synaptomes originating from sfxn3 KO mice. Nevertheless this could be explained by functional redundancy since all members of the sideroflexins are found in brain. Mutant proteins involved in neurodegenerative disorders tend to form aggregates inducing a stress of the endoplasmic reticulum (ER). Interestingly it has been recently shown that SFXN1 interacts with SCIRR69. SCIRR69 is a protein found at the ER and induced upon ER stress. Thus, considering that few data exist concerning SFXNs and that these proteins are associated with diseases where mitochondria are largely involved, we expect to give answers to some questions: What are the basal activities of SFXNs at the mitochondria? Are they important for mitochondrial respiration or do they regulate mitochondrial dynamics? Are they involved in response to diverse stress that converge to mitochondria (genotoxic or ER stress for example)?