The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1

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

doi:10.15252/embr.201948754

The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1

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

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

47 Citations (Scopus)

194 Downloads (Pure)

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.

Original language	English
Article number	e48754
Number of pages	16
Journal	EMBO Reports
Volume	23
Issue number	2
Early online date	7 Jan 2022
DOIs	https://doi.org/10.15252/embr.201948754
Publication status	Published - 3 Feb 2022

Bibliographical note

Funding Information:
Start‐up fund (BMS314826 to CG), Royal Society Research Grant (R/157589 to CG) and a PhD studentship (BMS315637 to EW) from the Department of Biomedical Science at the University of Sheffield supported this work. We are also grateful to BBSRC (BB/R00787X to KAW) and Parkinson’s UK (G‐1605 to REC) for financial support. We thank C Smythe for critical reading of the manuscript, C Smythe, GJ Cooper, L Robson, AC Lin, B Davletov, S Brown and MO Collins for great logistical support help, and EH Hettema for generous technical help with initial imaging experiments. We thank JM Henley and C Li for supplying plasmids and RT Hay for supplying the HEK293 N3S cells.

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

Fis1
mitophagy
organellar stress
SENP3
SUMO

Access to Document

10.15252/embr.201948754

Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via EMBO Press at https://doi.org/10.15252/embr.201948754 . Please refer to any applicable terms of use of the publisher.
Final published version, 2.09 MBLicence: CC BY

Handle.net

Persistent link

Cite this

@article{7cb6711f523d4f7c8b3282cb8aed93b4,

title = "The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1",

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.",

keywords = "Fis1, mitophagy, organellar stress, SENP3, SUMO",

author = "Emily Waters and Wilkinson, \{Kevin A\} and Harding, \{Amy L\} and Carmichael, \{Ruth E\} and Darren Robinson and Colley, \{Helen E.\} and Chun Guo",

note = "Funding Information: Start‐up fund (BMS314826 to CG), Royal Society Research Grant (R/157589 to CG) and a PhD studentship (BMS315637 to EW) from the Department of Biomedical Science at the University of Sheffield supported this work. We are also grateful to BBSRC (BB/R00787X to KAW) and Parkinson{\textquoteright}s UK (G‐1605 to REC) for financial support. We thank C Smythe for critical reading of the manuscript, C Smythe, GJ Cooper, L Robson, AC Lin, B Davletov, S Brown and MO Collins for great logistical support help, and EH Hettema for generous technical help with initial imaging experiments. We thank JM Henley and C Li for supplying plasmids and RT Hay for supplying the HEK293 N3S cells. Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2022",

month = feb,

day = "3",

doi = "10.15252/embr.201948754",

language = "English",

volume = "23",

journal = "EMBO Reports",

issn = "1469-221X",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "2",

}

TY - JOUR

T1 - The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1

AU - Waters, Emily

AU - Wilkinson, Kevin A

AU - Harding, Amy L

AU - Carmichael, Ruth E

AU - Robinson, Darren

AU - Colley, Helen E.

AU - Guo, Chun

N1 - Funding Information: Start‐up fund (BMS314826 to CG), Royal Society Research Grant (R/157589 to CG) and a PhD studentship (BMS315637 to EW) from the Department of Biomedical Science at the University of Sheffield supported this work. We are also grateful to BBSRC (BB/R00787X to KAW) and Parkinson’s UK (G‐1605 to REC) for financial support. We thank C Smythe for critical reading of the manuscript, C Smythe, GJ Cooper, L Robson, AC Lin, B Davletov, S Brown and MO Collins for great logistical support help, and EH Hettema for generous technical help with initial imaging experiments. We thank JM Henley and C Li for supplying plasmids and RT Hay for supplying the HEK293 N3S cells. Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022/2/3

Y1 - 2022/2/3

N2 - 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.

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 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.

KW - Fis1

KW - mitophagy

KW - organellar stress

KW - SENP3

KW - SUMO

U2 - 10.15252/embr.201948754

DO - 10.15252/embr.201948754

M3 - Article (Academic Journal)

C2 - 34994490

SN - 1469-221X

VL - 23

JO - EMBO Reports

JF - EMBO Reports

IS - 2

M1 - e48754

ER -

The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1

Abstract

Bibliographical note

Keywords

Access to Document

Handle.net

Fingerprint

Cite this