The role of mitochondrial protein BNIP3L/NIX phosphorylation and dimerisation in mitophagy activation (CROSBI ID 693175)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa
Podaci o odgovornosti
Marinković, Mija ; Buljubašić, Maja ; Šprung, Matilda ; Novak, Ivana
engleski
The role of mitochondrial protein BNIP3L/NIX phosphorylation and dimerisation in mitophagy activation
Cellular homeostasis requires a proper balance between synthesis and degradation of cellular content. The two major degradative pathways in eukaryotic organisms are autophagy and the proteasome. Here, we will focus on autophagy, a conserved survival mechanism which acts as an adaptive response to environmental conditions such as starvation. With the discovery of the autophagy-related (ATG) genes in yeast many additional physiological processes have been linked to autophagy including maintenance of cellular and tissue homeostasis, aging, differentiation and development, innate and adaptive immunity. In addition to ATP production, mitochondria regulate calcium homeostasis, heme biosynthesis and cell survival/death decisions. Their dysfunction has been implicated in numerous conditions, including cancer, metabolic diseases, neurodegeneration, diabetes and aging. Mitophagy, the selective removal of damaged mitochondria through autophagy, is thus crucial for maintaining proper cellular functions. Indeed, mitophagy has been proposed to play critical roles in terminal differentiation of erythrocytes, paternal mitochondrial degradation, neurodegenerative diseases and cancer. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors such as BNIP3, NIX/BNIP3L or FUNDC1. Discoveries of autophagic receptors that recognize specific cellular cargo have opened a new chapter in the autophagy field. Growing evidence of the function of particular autophagy receptors indicates that most of them are often working together in the same selective autophagy pathway, such as aggrephagy, xenophagy and mitophagy. In this part, we focused our research on receptors involved in mitophagy and their regulation. These receptors, such as scAtg32, BNIP3 and BNIP3L/NIX interact with Atg8/LC3/GABARAP family proteins in LIR-dependent manner and recruit autophagy machinery to damaged mitochondria. The lessons from xenophagy are directing future research towards better understanding of how mitophagy is activated and regulated. After all, this is not surprising because there is a well-accepted endosymbiotic theory that connects bacteria and mitochondria, where mitochondria are bacterial evolutionary descendants. Our results suggest that mitophagic function of NIX receptor is regulated by two possible mechanisms phosphorylation and homodimerisation. We showed cellular, biochemical and biophysical evidence that phosphorylation of LIR domain of 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. Another mechanism of NIX regulation is dimerisation via its transmembrane domain and we showed that Nix dimmers stronger recruite autophagosomes on damaged mitochondria. Understanding of mitophagy, and general autophagy regulation, is the major challenge for researchers of our time and their answers will help us to better understand the role of receptors and autophagy in disease development such as Parkinson`s disease and a number of other diseases.
Mitophagy ; NIX ; dimerization ; phosphorylation
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Podaci o prilogu
1-1.
2017.
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objavljeno
Podaci o matičnoj publikaciji
the EACR-FEBS advanced lecture course Molecular Mechanisms in Signal Transduction and Cancer
Podaci o skupu
Spetses Summer School an EACR-FEBS advanced lecture course „Molecular Mechanisms in Signal Transduction and Cancer“
poster
16.08.2017-24.08.2017
Spétses, Grčka