OSSIDO NITRICO E MITOCONDRI: NUOVE REGOLAZIONI E FUNZIONI NELLA FISIOLOGIA DEL MUSCOLO SCHELETRICO
Tesi di Dottorato
Data di Pubblicazione:
2012
Citazione:
OSSIDO NITRICO E MITOCONDRI: NUOVE REGOLAZIONI E FUNZIONI NELLA FISIOLOGIA DEL MUSCOLO SCHELETRICO / S. Pisoni ; tutor: E. Clementi ; correlatore: C. De Palma ; coordinatore: A. Panerai. Universita' degli Studi di Milano, 2012 Feb 03. 24. ciclo, Anno Accademico 2011.
Abstract:
Mitochondria are highly dynamic organelles that continuously and reversibly rearrange
their structure through the tightly-regulated processes of fission and fusion of their
inner and outer membranes. During myogenic differentiation short mitochondria of
myoblasts change into an elongated network observed in myotubes. Mitochondrial
elongation is required for myogenesis to occur and this event depends on cellular
generation of nitric oxide (NO). When NO pathway is blocked, mitochondria fragment and
display a latent dysfunction. Despite the apoptotic behaviours of mitochondria, myoblasts
don’t undergo apoptosis. Recently it has been demonstrated that, in skeletal muscle
dysfunctional mitochondria are degraded by an autophagic process, called mitophagy,
mediated by the AKT/FoxO3 pathway. Here, we investigate the induction of mitophagy
during muscle differentiation and its role in preventing apoptosis. We observe
mitochondrial fission in the presence of inhibitors of NO pathway and this accounts for
inhibition of the myogenic programme of myoblasts. Fragmentation causes a latent
mitochondrial dysfunction and reduces ATP production. Despite these apoptotic features,
cells don’t undergo apoptosis and only in presence of 3MA that blocks lysosomal
degradation we can detect annexin V positive cells. Dysfunctional mitochondria are
degraded by the activation of autophagy; in this condition the phosphorylation levels of
Akt and FoxO3 are reduced, as a clear sign of mitophagy induction. These results
demostrate the involment of FoxO3 pathway on autophagy regulation. We observed the
same results also on nNOS-KO in vivo model that show fragmented mitochondria,
reduction of myogenic differentiation and increase of autophagy.
Tipologia IRIS:
Tesi di dottorato
Keywords:
mitochondria ; autophagy ; skeletal muscle
Elenco autori:
S. Pisoni
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