[Seminar] Frataxin knockdown in Drosophila alters mitochondrial homeostasis and degradation in muscles and glia

Seminar

Protagoras Seminar Room (LAO Building, 2nd Floor)

Title: Frataxin knockdown in Drosophila  alters mitochondrial homeostasis and degradation in muscles and glia

Speaker: Juan Navarro

Affiliation: Institut für Zoologie, Universität Regensburg, Germany

Host: Colin Adrain/Pedro Domingos, Cell Signaling in Drosophila Lab

Abstract:

Frataxin is a highly conserved mitochondrial protein that participates in the biosynthesis of iron-sulfur clusters. Effects of frataxin downregulation in disease models of Friedreich Ataxia (FA) include diminished activity of several mitochondrial enzymes, impaired ATP production and depolarization of mitochondrial membrane among others. Drosophila models of FA have been able to reproduce all this biochemical features. In our study we aim to analyze the effect of frataxin depletion on mitochondrial dynamics and homeostasis in glial cells and indirect flight muscles (IFM). We are studying whether cells suffering from an energy deprivation due to loss of frataxin would modify their mitochondrial network to compensate the defect. Frataxin depletion affects mitochondrial morphology in both tissues as well as induces a significant increase of Ref(2)P levels which accumulates in vesicle-like structures. Ref(2)P is the Drosophila homolog of mammalian p62, a cargo protein involved in delivering damaged proteins and organelles to the autophagosome. The initial recruitment of Ref(2)P suggests an activation of mitophagy. However, the substantial and continuous accumulation of Ref(2)P in our model may indicate an impaired mitophagy in the etiology of FRDA. We are trying now to decipher the underlying mechanisms. By means of genetic interactions, we are modifying the mitochondrial network in order to find a factor that exacerbate or suppress the frataxin-deficient defects. Our results indicate that changes in the expression of Drosophila mitofusin (Mfn) might be a central event. Interestingly, Mfn plays important roles in mitochondrial fusion, mitochondrial degradation and ER-mitochondria tethering. We are currently investigating the influence of each of this functions on the FA phenotypes. Altogether, our results demonstrate that Drosophila IFM are an excellent tissue to dissect downstream effects of frataxin depletion. In this work, we describe for the first time an effect of frataxin knockdown on mitophagy and link frataxin with the homeostasis of mitochondria providing new ideas for the development of potential therapeutic targets.