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Identifier

000453374

Title

Investigating the role of the NEET protein family in ageing and neurodegeneration of the nematode Caenorhabditis elegans

Alternative Title

Μελέτη του ρόλου των πρωτεϊνών της οικογένειας NEET στη γήρανση και το νευροεκφυλισμό του νηματώδους Caenorhabditis elegans

Author

Πλουμή Χριστίνα

Thesis advisor

Ταβερναράκης, Νεκτάριος

Reviewer

Αλεξανδράκη, Δέσποινα
Δελιδάκης, Χρήστος
Βόντας, Ιωάννης
Καραγωγέως, Δόμνα
Χαμηλός, Γεώργιος
Παληκαράς, Κωνσταντίνος

Abstract

NEET family comprises a special type of Iron Sulfur Cluster (ISC) binding proteins implicated in various human pathologies ranging from neurodegeneration to cancer and reduced life expectancy. Despite the well-known structural and functional characteristics of mammalian NEETs, it remains largely enigmatic how their deficiency accelerates ageing and contributes to the manifestation of age-related pathologies. In our study we used the nematode Caenorhabditis elegans as a simple model organism to delineate the molecular pathways through which NEETs mediate their effects on longevity and healthspan. The nematode’s genome encodes for three NEET proteins: CISD-1, CISD-3.1 and CISD-3.2. CISD-1 is a single ortholog for both mammalian CISD1/mitoNEET and CISD2/Miner1, as it has one CDGSH domain for binding to ISCs. CISD-3.1 and CISD-3.2 have 2 CDGSH domains and thus are homologous to mammalian CISD3/MiNT. Our study is mainly focused on CISD-1, since its mammalian ortholog CISD2/Miner1 has been associated with Wolfram syndrome type 2, a rare neurodegenerative disorder characterized by premature ageing phenotypes. CISD-1 is a ubiquitously expressed protein localized at the outer mitochondrial membrane. CISD-1 deficient nematodes display reduced lifespan, enhanced neurodegeneration and exacerbated proteostasis. Our data reveal that CISD-1 preserves longevity through the mitochondrial intrinsic apoptosis pathway. Notably, the detrimental consequences of CISD-1 deficiency on lifespan, neuronal integrity and proteostasis are fully rescued upon depletion of the anti-apoptotic Bcl-2 nematode ortholog, CED-9. This rescue is dependent on autophagy induction, suggesting that CISD-1 mediates its effects by coupling the apoptosis and autophagic pathways through CED-9. In an attempt to further investigate the molecular function of CISD-1, we found that CISD-1 deficiency disturbs iron homeostasis, as evident by reduced Fe2+/Fetotal ratio in mitochondria, elevated ferritin expression and deregulated expression of iron-related genes. Importantly, our data suggest that intracellular iron abundance is critical for CISD-1 function, since mild iron supplementation is sufficient to decelerate ageing and partly ameliorates the disturbed proteostasis and neuronal integrity upon CISD-1 deficiency. Our work establishes CISD1 as a mitochondrial effector engaging autophagy and apoptosis pathways, and demonstrates novel approaches which could potentially facilitate the development of effective therapeutic interventions against WS2 or related diseases.

Language

English

Subject

Apoptosis

Autophagy

Iron

Mitochondria

Wolfram syndrome

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