Abstract
Mitophagy, the selective degradation of mitochondria by autophagy, is crucial for the maintenance of healthy mitochondrial pool in cells. The critical event in mitophagy is the translocation of cytosolic Parkin, a ubiquitin ligase, to the surface of defective mitochondria. This study elucidates a novel role of SESN2/Sestrin2, a stress inducible protein, in mitochondrial translocation of PARK2/Parkin during mitophagy. The data demonstrates that SESN2 downregulation inhibits BECN1/Beclin1 and Parkin interaction, thereby preventing optimum mitochondrial accumulation of Parkin. SESN2 interacts with ULK1 (unc-51 like kinase 1) and assists ULK1 mediated phosphorylation of Beclin1 at serine-14 position required for binding with Parkin prior to mitochondrial translocation. The trigger for SESN2 activation and regulation of Parkin translocation is the generation of mitochondrial superoxide. Scavenging of mitochondrial superoxide lower the levels of SESN2, resulting in retardation of Parkin translocation. Importantly, we observe that SESN2 mediated cytosolic interaction of Parkin and Beclin1 is PINK1 independent but mitochondrial translocation of Parkin is PINK1 dependent. Together, these findings suggest the role of SESN2 as a positive regulator of Parkin mediated mitophagy.
Highlights
As the main source of ATP, mitochondria is deemed to be a critical player in the regulation of cellular processes like death and survival[1,2]
The results suggest that during mitophagy, PINK1 primes the mitochondrial translocation of Parkin and acts as the very first impulse in the process, it is SESN2 that facilitates this translocation by enhancing interaction between Parkin and Beclin[1], which is independent of PINK1
Reduction in phosphorylation of ULK1 was observed on downregulation of SESN2 expression which suggest that SESN2 regulates the activation of ULK1 (Fig. 4E). These results suggest SESN2 mediated activation of Beclin[1] through ULK1 mediated phosphorylation could be responsible for Beclin[1] and Parkin interaction eventually leading to Parkin translocation to damaged mitochondria
Summary
As the main source of ATP, mitochondria is deemed to be a critical player in the regulation of cellular processes like death and survival[1,2]. Deletion of PINK1 or Parkin results in mitochondrial dysfunction due to defective mitophagy indicating a central role of these molecular players in the functioning and turnover of mitochondria[9,10]. Sestrins are a highly conserved family of stress inducible antioxidant proteins present in 3 forms (SESN1, 2, 3) in mammals and are known to regulate autophagy and mitophagy related events in response to various cellular stresses[12,13,14]. Our findings shed light on a mechanistic role of SESN2 in the regulation of Parkin mediated mitophagy by aiding its translocation to the damaged mitochondria. In response to CCCP-induced mitochondrial damage, SESN2 facilitates Beclin[1] and Parkin interaction through ULK1 mediated Beclin[1] phosphorylation (serine-14) resulting in translocation of Parkin to the damaged mitochondria. The results suggest that during mitophagy, PINK1 primes the mitochondrial translocation of Parkin and acts as the very first impulse in the process, it is SESN2 that facilitates this translocation by enhancing interaction between Parkin and Beclin[1], which is independent of PINK1
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