engleski

Interplay between C terminal mitophagy receptor NIX phosphorylation and dimerization as a new mechanism of receptor­ mediated mitophagy regulation

A form of autophagy specialized for selective removal of mitochondria, mitophagy, is essential for elimination of dysfunctional mitochondria whose accumulation can lead to the development of neurodegenerative diseases and tumors. Programmed mitophagy of healthy mitochondria is crucial for differentiation of particular cell types, such as erythrocytes. Autophagy receptor BNIP3L/NIX is shown to be important for the removal of healthy mitochondria during terminal erythropoiesis but molecular mechanisms of selectivity are still unclear. Here, we have investigated BNIP3L/NIX dimerization and phosphorylation as a novel molecular mechanism underlying receptor­mediated mitophagy. Stable BNIP3L/NIX homodimers provide the formation of new and strong interactions between the receptor and autophagosomal protein, more robust recruitment of autophagosomes and efficient removal of mitochondria. This dimerization is achieved by specific Ser212 dephosphorylation located in the intermembrane mitochondrial space and has the same effect on mitophagy initiation and progression as LIR phosphorylation, previously published in: Marinković et al. (2021) Autophagy 17(5), 1232­1243 and Rogov V et al. (2017) Sci Rep 7, 1131. Thus, the interplay between BNIP3L/NIX phosphorylation and dimerization indicates that the combined mechanism of LIR phosphorylation and receptor dimerization is needed for proper BNIP3L/NIX­ dependent mitophagy initiation and progression. Currently, the focus of our research is in detailed analysis of interactions between BNIP3L/NIX and identified kinases and phosphatases to unveil upstream signaling pathways that trigger and regulate mitophagy especially in erythroid cell lines. Lastly, this knowledge of the molecular basis of BNIP3L/NIX ­dependent mitophagy regulation is crucial for better understanding the mechanisms of individual cell`s differentiation and the development of pathological conditions that underlie the disturbed mitophagy process.

BNIP3L/NIX ; mitophagy ; autophagy

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