Naslov
Regulation of NIX-mediated mitophagy by dimerization and phosphorylation

Autori
Marinković, Mija ; Šprung, Matilda ; Rogov, Vladimir ; Dötsch, Volker ; Dikic, Ivan ; Novak, Ivana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Gordon Research Conference: Autophagy in Stress, Development and DIsease / - , 2018, 1-1

Skup
Gordon Research Conference: Autophagy in Stress, Development and DIsease

Mjesto i datum
Lucca, Italija, 17.03.2018. - 23.03.2018

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Podatak o recenziji nije dostupan

Ključne riječi
mitophagy, autophagy, NIX

Sažetak
The selective removal of damaged or excess mitochondria, mitophagy, is crucial for maintaining mitochondria quality control, and globally, cellular homeostasis. Two steps are indispensable for this selective removal of mitochondria: induction of general autophagy and priming of selected mitochondria for autophagic recognition. Mitochondrial priming is mediated either by the PINK1-PARKIN signaling pathway or specific mitophagic receptors such as scAtg32, BNIP3, BCL2L13, FUNDC1, FKBP8, PHB2 and BNIP3L/NIX that interact with Atg8/LC3/GABARAP family proteins in LIR-dependent manner and recruit autophagy machinery to selected mitochondria. Previous studies have shown that autophagic receptors, in the most cases, work together in the similar selective autophagy pathway, such as aggrephagy, xenophagy and mitophagy. In the focus of our research is mitophagic receptor BNIP3L/NIX that plays a critical role in terminal differentiation of erythrocytes when complete mitochondrial content from the cell has to be removed. Our results suggest that mitophagic function of BNIP3L/NIX receptor is regulated, at least, by two possible mechanisms ; phosphorylation and homodimerization. Cellular, biochemical and biophysical evidence showed that phosphorylation of LIR domain of BNIP3L/NIX receptor enhances its interactions with Atg8/LC3/GABARAP family proteins on the autophagosomal membrane and is essential for mitophagy activation. Unfortunately we don`t know yet what is the trigger for LIR phosphorylation and activation of mitophagy. The second mechanism of BNIP3L/NIX regulation is dimerization via its transmembrane domain and our preliminary results suggest that BNIP3L/NIX homodimers recruit autophagosomes stronger than BNIP3L/NIX monomers on damaged mitochondria. Moreover, we have identified several amino acid residues in the BNIP3L/NIX transmembrane domain that are responsible for dimerization and whose substitutions lead to abolishment of the dimer formation resulting in the lower LC3/GABARAP- BNIP3L/NIX recognition and subsequently lower mitophagy induction. The latest results suggest that mitophagy initiation and progression could be achieved throught the interplay between phosphorylation and dimerization of BNIP3L/NIX receptor. Understanding of mitophagy, and general autophagy regulation, is the major challenge for researchers.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA