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Trevisan, Tatiana (2016) Ruolo della morfologia e della funzionalità mitocondriale sulla distribuzione intracellulare dei mitocondri in neuroni di Drosophila. [Tesi di dottorato]

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Abstract (inglese)

ABSTRACT
Mitochondria are the energy producing organelles in eukaryotic cells providing ATP through oxidative phosphorylation (OXPHOS). Mitochondria are highly dynamic and undergo fission, fusion and move into the cell along the microtubules to generate the mitochondrial network. Mitochondrial dynamics play a critical role in the control of organelle shape, size, number, function and quality control of mitochondria. It is regulated by several GTPases that play an important role in fusion and fission processes. In mammals, mitochondrial fusion is controlled by Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2) and Optic atrophy protein 1 (Opa1), while mitochondrial fission is regulated by Dynamin related protein 1 (Drp1).
The aim of this study is to understand how mitochondrial distribution in neuronal cells is affected by mitochondria function and/or morphology. We use Drosophila melanogaster , whose genome contains homologs for all mitochondrial fusion and fission proteins, as a modelorganism to study how loss of fusion and fission protein modify the axonal distribution and motility of mitochondria. We demonstrate that loss of Marf (Mitochondrial associated regulatory factor, homologous to human mitofusins) or Opa1 causes an accumulation of mitochondria in the soma, a defect in the axonal distribution of mitochondria, a severe depletion of mitochondria in neuromuscular junctions (NMJs) and reduced mitochondrial motility. Simultaneous loss of Drp1 rescues the Opa1 phenotype very robustly while loss of Marf essentially does not.
Viability data however show the opposite trend. The expression of Marf RNAi or Opa1 RNAi cause lethality, and so does the double down regulation of Opa1 and Drp1. Conversely individuals expressing Marf RNAi and Drp1 RNAi simultaneously survive and are comparable to the controls. We then examined possible alterations of mitochondrial function by analyzing the mitochondrial respiratory capacity, the activity of the respiratory chain complexes and ATP production capacity. The data show that individuals where Marf, Opa1 or simultaneously Opa1 and Drp1 are down-regulated display severe alterations in mitochondrial function, while there are no obvious energy defects in individuals in which the expression of Marf and Drp1 is simultaneously reduced.
Collectively our results obtained suggest that mitochondrial morphology is important for a homogeneous distribution of mitochondria along the axon and their transport to synapses and that these mechanisms are independent of mitochondria function.

Abstract (italiano)

RIASSUNTO

I mitocondri sono organelli essenziali per la cellula e la loro funzione primaria è di produrre energia sottoforma di ATP. I mitocondri sono organelli altamente dinamici:processi di fusione e fissione delle membrane mitocondriali ne controllano la forma, la lunghezza e il numero e un equilibrio tra i due meccanismi è fondamentale per una corretta morfologia mitocondriale. Numerose proteine sono coinvolte nei processi di fusione e fissione mitocondriale: Mitofusina 1 e Mitofusina 2 (Mfn1 e Mfn2) e Optic atrophy 1 (Opa1) regolano i processi di fusione mitocondriale, mentre Dynamin-related protein 1 (Drp1)mediala fissione.
Drosophila possiede il gene mitochondrial assembly regulatory factor (MARF), espresso in modo ubiquitario ed omologo al gene MFN2. Nel tessuto muscolare la riduzione di espressione di Marf induce frammentazione e alterazione della morfologia del mitocondrio. Inoltre, mutanti di Marf mostrano una severa deplezione dei mitocondri nelle giunzioni neuromuscolari (NMJs) ed un’alterazione della morfologia della giunzione caratterizzata dall’aumento nel numero e da una riduzione nella dimensione dei bottoni sinaptici.
Un altro aspetto della dinamica mitocondriale, oltre ai processi di fusione e fissione, è la motilità dei mitocondri, che deve essere altamente regolata soprattutto in cellule come i neuroni. Il trasporto mitocondriale e la continua ridistribuzione dei mitocondri lungo l’assone è essenziale per il mantenimento dell’integrità assonale e delle normali funzioni della cellula. Studi hanno messo in evidenza come la mancanza di mitocondri a livello delle giunzioni neuromuscolari in Drosophila comprometta la trasmissione sinaptica e come difetti nel trasporto mitocondriale assonale siano implicati nello sviluppo di disordini neurologici e malattie neurodegenerative (Chan, 2006).
Lo scopo di questo lavoro è quello di capire il ruolo della morfologia e della funzione mitocondriale nella distribuzione intracellulare dei mitocondri nei neuroni. Per fare questo abbiamo utilizzato Drosophila melanogaster, organismo modello efficace per l’analisi della funzione genica, inclusa quella di geni responsabili di patologie umane. L’analisi della morfologia mitocondriale è stata effettuata utilizzando linee di Drosophilache esprimono in vivo un transgene per RNA interference e che permette di ridurre l’espressione di geni endogeni coinvolti nei processi di fusione e fissione mitocondriale, quali Marf, Opa1 e Drp1. Abbiamo inoltre creato linee che esprimono contemporaneamente i trangeni per RNAi di Marf e Drp1 o Opa1 e Drp1, con lo scopo di bilanciare i meccanismi di fusione e/o fissione. Ci siamo soffermati in particolare sullo studio di due aspetti principali, la morfologia e la funzionalità mitocondriale, per capire se difetti nella morfologia e nella funzionalità mitocondriale siano collegate e concorrano insieme allo sviluppo di patologie.Numerose patologie neurodegenerative sono infatti caratterizzate da alterazioni del trasporto mitocondriale e spesso questo è associato a difetti nella morfologia e nella funzionalità mitocondriale. Per studiare la morfologia mitocondriale, le linee UAS-RNAi sono state incrociate con una linea che contiene il promotore ELAV per l’espressione tessuto-specifica nei neuroni ed esprime una GFP mitocondriale. Abbiamo analizzato la morfologia dei mitocondri, sia nel corpo cellulare sia negli assoni e la distribuzione mitocondriale in assoni lunghi come i motoneuroni e assoni corti come quelli del nervo ottico e la distribuzione mitocondriale nella giunzione neuromuscolare.I risultati ottenuti mostrano che frammentazione dei mitocondri e alterazione della distribuzione mitocondriale assonale in individui in cui sia ridotta l’espressione di proteine di fusione. Inoltre si osserva una diminuzione della percentuale dei mitocondri mobili e del numero assoluto dei mitocondri anterogradi e retrogradi. Questi dati dimostrano che vi è una stretta correlazione tra morfologia mitocondriale e distribuzione dei mitocondri, in particolare in assoni lunghi. Inoltre analizzando le linee Marf RNAi Drp1 RNAi e Opa1 RNAi Drp1 RNAi, nelle quali gli eventi di fusione e fissione ridotti ma sono in equilibrio tra loro, si osserva un miglioramento la morfologia, la distribuzione e il trasporto mitocondriale assonale in modo particolare nel caso di Opa1 e non nel caso di Marf.
Abbiamo cercato di capire quindi se in questi individui vi fossero alterazioni delle funzionalità mitocondriali attraverso l’analisi della capacità respiratoria mitocondriale, dell’attività dei complessi della catena respiratoria e della capacità di produzione di ATP. I risultati ottenuti dimostrano che morfologia e funzionalità mitocondriale non sempre sono collegate tra loro hanno effetti diversi nella modulazione della distribuzione mitocondriale assonale. In conclusione possiamo affermare che solamente la morfologia e la dimensione del mitocondrio sembrano essere essenziali per la corretta distribuzione mitocondriale assonale.

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Tipo di EPrint:Tesi di dottorato
Relatore:Montopoli, Monica - Daga, Andrea
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > SCIENZE FARMACOLOGICHE > FARMACOLOGIA MOLECOLARE E CELLULARE
Data di deposito della tesi:29 Gennaio 2016
Anno di Pubblicazione:29 Gennaio 2016
Parole chiave (italiano / inglese):mitocondri, processo fusione e fissione mitocondriale, mitofusina, Opa1, Drp1 mitochondria, mitochondria fusion and fission mechanisms, mitofusin, Opa1, Drp1
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:9376
Depositato il:06 Ott 2016 14:47
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