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Bettio, Sara (2014) Ruolo dell'autofagia e della dinamica mitocondriale nella segregazione del DNA mitocondriale. [Tesi di dottorato]

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Abstract (inglese)

ABSTRACT
Mitochondrial DNA is maternally inherited and its copy number can reach thousand per cell. Phatological mutations of human mtDNA have been known for many years and mutant mtDNA molecules frequently co-exist with wild-type copies of mtDNA. The most common point of mutation is adenine to guanine transition at nucleotide position (nt) 3243 of human mtDNA that is associated with the neuromuscular disease MELAS. How deleterious mtDNA mutations become established, and how they wax and wane over the course of the time are matters of intense investigation. Several reports have suggested that mutant mtDNA become fixed purely by the stochastic process of genetic drif. However, recent study in mouse suggest that a purification, selection process, operates in germline to week out deleterious mtDNA variants. The distribution of A3243G mtDNA in patients with mitochondrial disease was found to be non-random in on study. Thus, there is ample evidence that mutant load is not merely determined by random genetic drift. The segregation and transmission of mtDNA is dependent on mitochondrial movement and elimination. Even in non-dividing cells mitochondria are dynamic undergoing fusion and fission; they range from small spherical structures to complex interconnected networks. The extent of the network depends on the balance between elongation and fragmentation of mitochondria. In our laboratory was demonstrated that altering the balance between mitochondrial fission and fusion influences the segregation of mutant and wild-type mtDNA variants, suggesting that the level of mutant and wild-type mitochondrial DNA can be manipulated by alteing expression of nuclear encodedfactors involved in mitochondrial fission and mitochondrial quality control (mtQC). The goals of the project are i) the clarify the relationship between mutant mtDNA segregation and mitochondrial dynamics with a manipulation of the mitochondrialfusion by Mitofusin1 gene silencing and ii) study the autophagic and mitophagic machinery in cells with different proportion of MELAS mutant mtDNA : lung cybrids (0%, 35, 70%, 99% mutant) and muscle cybrids (0%,70%,80%,99%).
Since lung (A549 adenocarcinoma) cybrids favour wild-type mtDNA and muscle (RD rhabdomyosarcoma) cybrids favour mutant mtDNA.In this work we have obtained the downregulation of Mfn1 in six clones of RD cybrids harbouring 80% mutant load by using RNAi method.In these clones a decrease of mutant mtDNA molecules wasn’t observed.
Autophagywas tested by quantifying expression e protein levels of the autophagic markers LC3 and p62.. We found that both the proteins were well rapresented in both the cells harbouring A3243G mutant mtDNA with different nuclear background , indicating a good autophagy in both cell lines with no differences linked to the nuclear background;.
We analysed the sequestration, sorting and elimination of damage mitochondria by quantifying expression and protein level of the mitophagic markers PINK1, Parkin and BNIP3 atmorphological, biochemical and molecular level.
All the data demonstrated that in lung cybrids the mitophagy increased with the increase of mutant load, indicating an active elimination of damaged mitochondria. Interesting in muscle cybrids occurred the opposite: the mitophagic process decreased with the increase of mutant load. These data clarify that in muscle background the mutant mtDNA is favored since mitophagy is altered.compare lung cybrids.

Abstract (italiano)

RIASSUNTO
Il DNA mitocondriale ha una trasmissione matrilineare ed ogni cellula contiene tra le 500 e le 10000 molecole di mtDNA. Le mutazioni patologiche dell’mtDNA umano sono conosciute da numerosi anni ed è noto che le molecole di DNA mitocondriale mutato e wild-type coesistono all’interno della stessa cellula, condizione nota come eteroplasmia. La mutazione puntiforme più comune è la mutazione A3243G nel gene tRNA Leu(UUR) del DNA mitocondriale umano ed è associata alla sindrome MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). In che modo le mutazioni dannose dell’mtDNA si stabilizzino, e come crescano e diminuiscano con il passare del tempo sono argomenti di grande interesse e che richiedono ancora notevole studio. Diversi articoli suggeriscono che il DNA mitocondriale mutato si fissa solamente attraverso un processo stocastico. Comunque studi recenti condotti su topo hanno dimostrato che a livello germinale vi è una purificazione, un processo selettivo, per eliminare le varianti dannose. Ed un altro studio un altro ha evidenziato che la distribuzione della mutazione A3243G nell’mtDNA di pazienti affetti da malattia mitocondriale non era casuale. C’è quindi una forte evidenza che la quantità di mutazione non è solamente determinata da un processo casuale di deriva genetica. La segregazione e la trasmissione dell’mtDNA sono dipendenti dai movimenti mitocondriali e dalla loro eliminazione. Anche in cellule che non si dividono i mitocondri sono organelli dinamici che sottostanno ad eventi di fissione e fusione; essi oscillano da una struttura piccola e sferica ad una complessa rete interconnessa. L’estensione di questa rete dipende dall’equilibrio tra elongazione e frammentazione dei mitocondri. Nel nostro laboratorio è stato dimostrato che perturbando l’equilibrio tra la fissione e la fusione mitocondriale viene influenzata la segregazione dell’mtDNA wild-type e mutato, suggerendo che i livelli di DNA mitocondriale wild-type e mutato possono essere manipolati dall’alterazione dell’espressione di fattori nucleari codificanti per proteine coinvolte nella fissione e nel controllo di qualità mitocondriale (mtQC). Lo studio ha avuto come obbiettivi: i) chiarificare la relazione tra la segregazione dell’mtDNA mutato e la dinamica mitocondriale grazie alla manipolazione della fusione mitocondriale silenziando geneticamente Mitofusina1 e ii) studiare il macchinario autofagico e la mitofagia in cellule con una diversa percentuale di mutazione MELAS dell’mtDNA: cibridi di polmone (0%, 35%, 70% e 99% mutati) e cibridi di muscolo (0%, 70%, 80% e 99% mutati). Poiché i cibridi di polmone (A549 adenocarcinoma polmonare) favoriscono l’mtDNA wild-type e i cibridi di muscolo (RD rabdomiosarcoma) favoriscono il DNA mitocondriale mutato.
In questo lavoro abbiamo ottenuto la down regolazione di Mfn1 in sei cloni di cibridi RD con l’80% di mutazione utilizzando la tecnica dell’RNAi. In questi cloni non è stato osservato un decremento delle molecole di mtDNA mutate. L’autofagia è stata analizzata quantificando l’espressione genica e la quantità di proteina dei principali markers quali: p62 e LC3. Abbiamo scoperto che entrambe le proteine sono presenti nelle due linee cellulari con mutazione A3243G dell’ mtDNA e diverso background nucleare, indicando che vi è una buona “auto pulizia” in entrambe le linee cellulari e che non vi sono differenze legate al background nucleare. Abbiamo analizzato anche l’eliminazione specifica dei mitocondri danneggiati, mitofagia, quantificando l’espressione genica e i livelli di proteina di tre markers mitofagici: PINK1, Parkin e BNIP3. Inoltre sono state condotte analisi morfologiche, biochimiche e molecolari sempre per valutare sia l’autofagia che la mitofagia. Tutti i dati dimostrano che nei cibridi di polmone la mitofagia aumenta con l’aumentare del DNA mitocondriale mutato, indicando che vi è una attiva rimozione dei mitocondri danneggiati. Interessante è notare che nei cibridi muscolari si verifica l’opposto: la mitofagia diminuisce all’aumentare della percentuale di mutazione. Questi dati ci spiegano perchè nei cibridi con background muscolare viene favorito il DNA mitocondriale mutato, e mostrano come possibile causa di questo comportamento la presenza di una mitofagia alterata e meno efficiente rispetto a quella dei cibridi con background polmonare.

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Tipo di EPrint:Tesi di dottorato
Relatore:Vergani, Lodovica
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > FISIOPATOLOGIA CLINICA E SCIENZE NEFROLOGICHE
Data di deposito della tesi:29 Gennaio 2014
Anno di Pubblicazione:29 Gennaio 2014
Parole chiave (italiano / inglese):segregazione, mitofagia, autofagia, mtDNA, mitocondri
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Struttura di riferimento:Dipartimenti > Dipartimento di Neuroscienze
Codice ID:6606
Depositato il:14 Nov 2014 14:30
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