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Di Marco, Giulia (2018) The role of MitokATP in skeletal muscle. [Tesi di dottorato]

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Abstract (inglese)

Mitochondria ATP-sensitive potassium channels (mitoKATP) were first described in 1991 by direct patch clamp of isolated mitoplasts. Different approaches have been used to characterize the pharmacological profile of the channel. These studies strongly support the idea that cellular protection from damage well correlates with the opening of mitoKATP. Indeed, pharmacological activation of the mitoKATP can efficiently protect the heart from ischemia/reperfusion injury. However, despite its huge therapeutic potential, the molecular identity of the mitoKATP is still unknown. In my laboratory, a novel protein complex that recapitulates the main electrophysiological features and the pharmacological profile of mitoKATP has been identified. In particular, it has been demonstrated that the mitoKATP is a heteroligomer composed by a tetramer of mitochondrial K+ channel forming subunits (mitoK) associated with four ATP-sensitive regulatory subunits (mitoSUR) arranged in an octameric complex.
MitoKATP is believed to act as a sensor of the cellular metabolic state. While in physiological conditions, i.e. when ATP is abundant, it remains mainly closed, a decrease in intracellular ATP levels triggers its opening, an event considered to be protective in a variety of stress conditions. However, although in stress condition the opening of mitoKATP channel is protective, in basal condition, when intracellular ATP concentration is sufficient, its constitutive activation is not favorable. Experiments performed in cells indicate that the overexpression of mitoK, the potassium permeant subunit of the channel, induces a decrease in mitochondrial Ca2+ transients evoked by agonist stimulation, a drastic reduction of mitochondria membrane potential, fragmentation of the mitochondrial network and derangement of the IMM ultrastructure, with the total collapse of the cristae. These severe changes in mitochondrial structure and function are due to the uncontrolled influx of K+ and the subsequent osmotically obligated water into the mitochondrial matrix. Indeed, the overexpression of the potassium channel forming subunit (mitoK) causes the constitutive opening of the mitoKATP channel, which is not anymore controlled by the ATP sensitive subunits. Overall, these data demonstrate that mitoK plays an important role in the control of mitochondria structure and function. Due to the importance of mitochondrial function in muscle homeostasis, we investigate the pathophysiological role of the mitoKATP in skeletal muscle. Firstly, we decided to investigate the effect of mitoK overexpression during post-natal development. For this purpose, newborn mice were injected with AAV9 (Adeno Associated Virus Serotype 9) particles expressing mitoK (AAV9mitoK). Four weeks after infection, we observed a great reduction of muscle weight, which was due to decreased myofibers size. Electron microscopy analysis demonstrated alterations in the mitochondrial structure: the internal cristae were totally collapsed and mitochondria were swollen. Inside the organelles, many vacuoles were also present indicating that damaged mitochondria were being degraded. In skeletal muscle mitoK overexpression induces a broad stress response, as indicated by the expression profile of specific genes, and activates cell proteolytic pathways to eliminate damaged organelles and dysfunctional proteins. Mitok overexpressing muscles were also characterized by a great increase in protein polyubiquitination and a block of the late stage of autophagic flux. As compensatory mechanism to counteract muscle wasting, protein synthesis was activated and IGF/AKT pathway, one of the major signalling pathways involved in the control of muscle mass, was induced. Taken together our results indicate that mitoK plays a role on the control of muscle mitochondria function and on muscle trophism.

Abstract (italiano)

I canali mitochondriali del potassio sensibili all’ATP (mitoKATP) sono stati descritti per la prima volta nel 1991 in seguito ad esperimenti di patch clamp su mitoplasti isolati. Diversi approcci sono stati utilizzati per caratterizzare il profilo farmacologico di questi canali. Questi studi sostengono fortemente l'idea che l'apertura di mitoKATP sia correlata con la protezione cellulare da danni. In particolare, l’attivazione farmacologica del mitoKATP può efficientemente proteggere il cuore dal danno da ischemia/riperfusione. Tuttavia, nonostante il loro enorme potenziale terapeutico, la composizione molecolare dei canali mitoKATP è ancora sconosciuta. Nel mio laboratorio è stato identificato un nuovo complesso proteico in grado di riassumere le principali caratteristiche elettrofisiologiche e il profilo farmacologico del mitoKATP. In particolare, abbiamo dimostrato che il canale mitocondriale del potassio è un eteroligomero, organizzato in una struttura ottamerica, composto da un tetramero di subunità permeabili al catione potassio e da quattro subunità regolatorie sensibili all’ATP.
Si ritiene che i mitoKATP siano in grado di agire da sensori dello stato metabolico cellulare. Mentre in condizioni fisiologiche, quando l’ATP disponibile è sufficiente, i canali restano chiusi, una riduzione dei livelli intracellulari di ATP causa la loro apertura, evento considerato protettivo in varie condizioni di stress cellulare. Tuttavia, nonostante in condizioni di stress cellulare l’attivazione di mitoKATP risulti vantaggiosa, in condizioni basali, quando la concentrazione intracellulare di ATP è sufficiente, l’apertura non controllata del canale risulta dannosa. Esperimenti svolti in cellule indicano che la sovraespressione di mitoK, la subunità del canale sensibile al potassio, induce una riduzione dell’accumulo mitocondriale dello ione calcio in risposta a stimoli, una drastica riduzione del potenziale di membrana mitocondriale e la frammentazione della morfologia mitocondriale caratterizzata dalla perdita totale delle creste.
Questi drastici cambiamenti della struttura e della funzione cellulare, sono dati dall’incontrollato influsso di potassio e da una conseguente entrata di acqua per osmosi all’interno della matrice mitocondriale. Infatti, la sovraespressione della subunità del canale permabile al potassio (mitoK) causa una costitutiva apertura del canale, il quale non risulta più controllato dalle subunità regolatorie ATP-sensibili. Nel complesso, i nostri dati indicano che mitoK svolge un ruolo importante nel controllo della funzione e della struttura mitocondriale.
Data l’importanza della corretta funzionalità mitocondriale nel mantenimento dell’omeostasi muscolare, abbiamo indagato il ruolo patofisiologico dei mitoKATP nel muscolo scheletrico. Come prima cosa abbiamo deciso di analizzare gli effetti della sovraespressione di mitoK durante lo sviluppo post-natale. A questo scopo abbiamo iniettato topi neonati con particelle di AAV9 (Virus Adeno Associato Serotipo 9) esprimenti mitok (AAV9mitoK). Quattro mesi dopo l’infezione abbiamo osservato un fenotipo fortemente atrofico, caratterizzato da una forte riduzione della grandezza delle fibre muscolari. Analisi di microscopia elettronica indicano che la sovraespressione di mitok altera la struttura mitocondriale: le cristae mitocondriali interne sono completamente collassate e i mitocondri appaiono rigonfi. All’interno degli organelli sono inoltre presenti molti vacuoli i quali suggeriscono l’attivazione di sistemi di degradazione dei mitocondri disfunzionali. Nel muscolo scheletrico, la sovraespressione di mitoK induce un’ampia risposta di stress cellulare che porta all’attivazione di sistemi di degradazione degli organelli danneggiati e delle proteine disfunzionali. Nei muscoli sovraesprimenti mitoK abbiamo infatti riscontrato un sostanziale aumento delle proteine ubiquitinate, destinate alla degradazione, ed un blocco delle fasi tardive del flusso autofagico. Per contrastare la perdita eccessiva di materiale citoplasmatico, nelle fibre muscolari viene incrementata la sintesi proteica e attivata una delle principali vie di segnalazioni cellulare implicata nel controllo della massa muscolare, la via IGF/AKT.
Nel complesso i nostri dati indicano che mitoK gioca un ruolo importante nel controllo della funzionalità mitocondriale nel muscolo e nel controllo del trofismo del muscolo scheletrico.

Tipo di EPrint:Tesi di dottorato
Relatore:Rizzuto, Rosario
Correlatore:De Stefani, Diego - Mammucari, Cristina
Dottorato (corsi e scuole):Ciclo 30 > Corsi 30 > SCIENZE BIOMEDICHE SPERIMENTALI
Data di deposito della tesi:12 Gennaio 2018
Anno di Pubblicazione:12 Gennaio 2018
Parole chiave (italiano / inglese):MitoKATP channel, skeletal muscle, muscle atrophy, mitochondrial dysfunction
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/04 Patologia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:10697
Depositato il:25 Ott 2018 15:49
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