The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1.

Emily Waters,Helen E Colley,Ruth E Carmichael,Chun Guo,Kevin A Wilkinson,Amy L Harding,Darren Robinson

doi:10.15252/embr.201948754

Emily Waters, Helen E Colley + Show 5 more

Open Access

https://doi.org/10.15252/embr.201948754

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Journal: EMBO Reports	Publication Date: Jan 7, 2022
Citations: 25	License type: CC BY 4.0

Affiliation: University of Sheffield, University of Bristol

Abstract

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 used 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 stabilization 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 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.

Highlights

Accurate and proper degradation of dysfunctional mitochondria by mitophagy is essential for maintaining control over mitochondrial quality and quantity
We show that levels of the Small Ubiquitin-like MOdifier protein (SUMO)-2/3specific deSUMOylating enzyme SENP3 are greatly stabilized upon DFP treatment via a pathway that involves the reduction in levels of the E3 ubiquitin (Ub)-protein ligase CHIP
To investigate if SENP3 is important for mitochondriacontaining autolysosome formation induced by DFP, we examined the role of SENP3 in mitophagic flux using mito-Keima, a wellestablished probe targeting the mitochondrial inner membrane for mitophagy detection (Sun et al, 2017), in living HeLa cells treated with DFP

Summary

Introduction

Accurate and proper degradation of dysfunctional mitochondria by mitophagy is essential for maintaining control over mitochondrial quality and quantity. Degradation of dysfunctional mitochondria occurs via a poorly understood quality control programme involving fission of dysfunctional organelles (Twig et al, 2008), their accumulation in autophagosomes with elevated levels of LC3 lipidation (Jimenez-Orgaz et al, 2018) and subsequent lysosomal fusion resulting in degradation (Sun et al, 2015). Accumulation of dysfunctional mitochondria is associated with both ageing (Green et al, 2011; Lopez-Otin et al, 2013; Biala et al, 2015; Gonzalez-Freire et al, 2015) and age-related diseases (Lionaki et al, 2015; Quiros et al, 2015; Wong & Holzbaur, 2015). Drp itself does not appear to be essential for mitophagy (Mendl et al, 2011; Song et al, 2015; Yamashita et al, 2016)

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