PT  - JOURNAL ARTICLE
AU  - Emily Waters
AU  - Kevin A. Wilkinson
AU  - Ruth E. Carmichael
AU  - Chun Guo
TI  - The SUMO Protease SENP3 regulates Mitochondrial Autophagy mediated by Fis1
AID  - 10.1101/685834
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 685834
4099  - http://biorxiv.org/content/early/2019/06/28/685834.short
4100  - http://biorxiv.org/content/early/2019/06/28/685834.full
AB  - Mitochondria are unavoidably subject to organellar stress resulting from exposure to a range of reactive molecular species. Consequently, cells operate a poorly understood quality control programme of mitophagy to facilitate elimination of dysfunctional mitochondria. Here we use a model stressor, deferiprone (DFP), to investigate the molecular basis for stress-induced mitophagy. We show that mitochondrial fission 1 protein (Fis1) is required for DFP-induced mitophagy and that Fis1 is SUMOylated at K149, an amino acid residue critical for Fis1 mitochondrial localization. We find that DFP treatment leads to the stabilisation of the SUMO protease SENP3, which is mediated by downregulation of the E3 ubiquitin (Ub) ligase CHIP. SENP3 is responsible for Fis1 deSUMOylation and depletion of SENP3 abolishes DFP-induced mitochondrial mitophagy. Furthermore, preventing Fis1 SUMOylation by conservative K149R mutation enhances Fis1 mitochondrial localization. Critically, expressing a Fis1 K149R mutant restores DFP-induced mitophagy in SENP3 depleted cells. Thus, we propose a model in which SENP3-mediated deSUMOylation facilitates Fis1 mitochondrial localization to underpin stress-induced mitophagy.