NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy

Tetsushi Kataura; Elsje G Otten; Yoana Rabanal-Ruiz; Elias Adriaenssens; Francesca Urselli; Filippo Scialo; Lanyu Fan; Graham R Smith; William M Dawson; Xingxiang Chen; Wyatt W Yue; Agnieszka K Bronowska; Bernadette Carroll; Sascha Martens; Michael Lazarou; Viktor I Korolchuk

doi:10.15252/embj.2022111372

NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy

Tetsushi Kataura, Elsje G Otten, Yoana Rabanal-Ruiz, Elias Adriaenssens, Francesca Urselli, Filippo Scialo, Lanyu Fan, Graham R Smith, William M Dawson, Xingxiang Chen, Wyatt W Yue, Agnieszka K Bronowska, Bernadette Carroll, Sascha Martens, Michael Lazarou, Viktor I Korolchuk

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

26 Citations (Scopus)

Abstract

Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.

Original language	English
Pages (from-to)	e111372
Journal	EMBO Journal
Early online date	14 Dec 2022
DOIs	https://doi.org/10.15252/embj.2022111372
Publication status	E-pub ahead of print - 14 Dec 2022

Bibliographical note

Funding Information:
We are grateful to Hanna Salmonowicz for graphical design; Glyn Nelson and Newcastle Bioimaging Unit for imaging assistance. This study was supported by Fellowships from Uehara Memorial Foundation and the International Medical Research Foundation to TK; FEDER (2018/D/LD/MC/8) to YR‐R; a Marie Skłodowska‐Curie MSCA Postdoctoral Fellowship to EA (101062916); a Wellcome Trust Fellowship (218547/Z/19/Z) to BC; the Austrian Science Fund (FWF SFB F79) to SM; NHMRC (GNT1106471, GNT1160315) and Australian Research Council (FT1601100063, DP200100347) to ML; BBSRC (BB/M023389/1) and BBSRC (BB/R008167/2) grants to VIK; Royal Society‐Newton Mobility Grant (IEC\NSFC\170125) to VIK and XC.

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

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Kataura, T., Otten, E. G., Rabanal-Ruiz, Y., Adriaenssens, E., Urselli, F., Scialo, F., Fan, L., Smith, G. R., Dawson, W. M., Chen, X., Yue, W. W., Bronowska, A. K., Carroll, B., Martens, S., Lazarou, M., & Korolchuk, V. I. (2022). NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy. EMBO Journal, e111372. Advance online publication. https://doi.org/10.15252/embj.2022111372

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title = "NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy",

abstract = "Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.",

author = "Tetsushi Kataura and Otten, {Elsje G} and Yoana Rabanal-Ruiz and Elias Adriaenssens and Francesca Urselli and Filippo Scialo and Lanyu Fan and Smith, {Graham R} and Dawson, {William M} and Xingxiang Chen and Yue, {Wyatt W} and Bronowska, {Agnieszka K} and Bernadette Carroll and Sascha Martens and Michael Lazarou and Korolchuk, {Viktor I}",

note = "Funding Information: We are grateful to Hanna Salmonowicz for graphical design; Glyn Nelson and Newcastle Bioimaging Unit for imaging assistance. This study was supported by Fellowships from Uehara Memorial Foundation and the International Medical Research Foundation to TK; FEDER (2018/D/LD/MC/8) to YR‐R; a Marie Sk{\l}odowska‐Curie MSCA Postdoctoral Fellowship to EA (101062916); a Wellcome Trust Fellowship (218547/Z/19/Z) to BC; the Austrian Science Fund (FWF SFB F79) to SM; NHMRC (GNT1106471, GNT1160315) and Australian Research Council (FT1601100063, DP200100347) to ML; BBSRC (BB/M023389/1) and BBSRC (BB/R008167/2) grants to VIK; Royal Society‐Newton Mobility Grant (IEC\NSFC\170125) to VIK and XC. Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",

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doi = "10.15252/embj.2022111372",

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T1 - NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy

AU - Kataura, Tetsushi

AU - Otten, Elsje G

AU - Rabanal-Ruiz, Yoana

AU - Adriaenssens, Elias

AU - Urselli, Francesca

AU - Scialo, Filippo

AU - Fan, Lanyu

AU - Smith, Graham R

AU - Dawson, William M

AU - Chen, Xingxiang

AU - Yue, Wyatt W

AU - Bronowska, Agnieszka K

AU - Carroll, Bernadette

AU - Martens, Sascha

AU - Lazarou, Michael

AU - Korolchuk, Viktor I

N1 - Funding Information: We are grateful to Hanna Salmonowicz for graphical design; Glyn Nelson and Newcastle Bioimaging Unit for imaging assistance. This study was supported by Fellowships from Uehara Memorial Foundation and the International Medical Research Foundation to TK; FEDER (2018/D/LD/MC/8) to YR‐R; a Marie Skłodowska‐Curie MSCA Postdoctoral Fellowship to EA (101062916); a Wellcome Trust Fellowship (218547/Z/19/Z) to BC; the Austrian Science Fund (FWF SFB F79) to SM; NHMRC (GNT1106471, GNT1160315) and Australian Research Council (FT1601100063, DP200100347) to ML; BBSRC (BB/M023389/1) and BBSRC (BB/R008167/2) grants to VIK; Royal Society‐Newton Mobility Grant (IEC\NSFC\170125) to VIK and XC. Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022/12/14

Y1 - 2022/12/14

N2 - Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.

AB - Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.

U2 - 10.15252/embj.2022111372

DO - 10.15252/embj.2022111372

M3 - Article (Academic Journal)

C2 - 36514953

SN - 0261-4189

SP - e111372

JO - EMBO Journal

JF - EMBO Journal

ER -

NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy

Abstract

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