Selective autophagy of mitochondria on a ubiquitin-endoplasmic reticulum platform

Maria Zachari, Sigurdur Gudmundsson, Ziyue Li, Maria Manifava, Ronak Shah, Matthew Smith, James Stronge, Eleftherios Karanasios, Caterina Piunti, Chieko Kishi-Itakura, Helena Vihinen, Eija Jokitalo, Jun-Lin Guan, Folma Buss, Andrew M. Smith, Simon A. Walker, Eeva-Liisa Eskelinen, Nicholas T. Ktistakis

Research output: Contribution to journalArticleScientificpeer-review

Abstract

The dynamics and co-ordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes, or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to address
these questions. Ubiquitination of mitochondrial fragments is required earliest followed by autophosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps whereas ULK1/2 are dispensable. Receptors act temporally and mechanistically upstream of
ATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way suggesting multiple initiation events. Targeted ubiquitinated mitochondrial are cradled by endoplasmic reticulum strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands providing platforms for formation of the mitophagosomes.
Original languageEnglish
JournalDevelopmental Cell
ISSN1534-5807
DOIs
Publication statusE-pub ahead of print - 15 Jul 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1182 Biochemistry, cell and molecular biology
  • autophagy
  • mitophagy
  • ivermectin
  • ubiquitin
  • endoplasmic reticulum

Cite this

Zachari, Maria ; Gudmundsson, Sigurdur ; Li, Ziyue ; Manifava, Maria ; Shah, Ronak ; Smith, Matthew ; Stronge, James ; Karanasios, Eleftherios ; Piunti, Caterina ; Kishi-Itakura, Chieko ; Vihinen, Helena ; Jokitalo, Eija ; Guan, Jun-Lin ; Buss, Folma ; Smith, Andrew M. ; Walker, Simon A. ; Eskelinen, Eeva-Liisa ; Ktistakis, Nicholas T. . / Selective autophagy of mitochondria on a ubiquitin-endoplasmic reticulum platform. In: Developmental Cell. 2019.
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title = "Selective autophagy of mitochondria on a ubiquitin-endoplasmic reticulum platform",
abstract = "The dynamics and co-ordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes, or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to addressthese questions. Ubiquitination of mitochondrial fragments is required earliest followed by autophosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps whereas ULK1/2 are dispensable. Receptors act temporally and mechanistically upstream ofATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way suggesting multiple initiation events. Targeted ubiquitinated mitochondrial are cradled by endoplasmic reticulum strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands providing platforms for formation of the mitophagosomes.",
keywords = "1182 Biochemistry, cell and molecular biology, autophagy, mitophagy, ivermectin, ubiquitin, endoplasmic reticulum",
author = "Maria Zachari and Sigurdur Gudmundsson and Ziyue Li and Maria Manifava and Ronak Shah and Matthew Smith and James Stronge and Eleftherios Karanasios and Caterina Piunti and Chieko Kishi-Itakura and Helena Vihinen and Eija Jokitalo and Jun-Lin Guan and Folma Buss and Smith, {Andrew M.} and Walker, {Simon A.} and Eeva-Liisa Eskelinen and Ktistakis, {Nicholas T.}",
year = "2019",
month = "7",
day = "15",
doi = "doi: 10.1016/j.devcel.2019.06.016",
language = "English",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",

}

Zachari, M, Gudmundsson, S, Li, Z, Manifava, M, Shah, R, Smith, M, Stronge, J, Karanasios, E, Piunti, C, Kishi-Itakura, C, Vihinen, H, Jokitalo, E, Guan, J-L, Buss, F, Smith, AM, Walker, SA, Eskelinen, E-L & Ktistakis, NT 2019, 'Selective autophagy of mitochondria on a ubiquitin-endoplasmic reticulum platform' Developmental Cell. https://doi.org/doi: 10.1016/j.devcel.2019.06.016

Selective autophagy of mitochondria on a ubiquitin-endoplasmic reticulum platform. / Zachari, Maria; Gudmundsson, Sigurdur; Li, Ziyue; Manifava, Maria; Shah, Ronak; Smith, Matthew; Stronge, James; Karanasios, Eleftherios; Piunti, Caterina; Kishi-Itakura, Chieko; Vihinen, Helena; Jokitalo, Eija; Guan, Jun-Lin; Buss, Folma; Smith, Andrew M.; Walker, Simon A.; Eskelinen, Eeva-Liisa; Ktistakis, Nicholas T. .

In: Developmental Cell, 15.07.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Selective autophagy of mitochondria on a ubiquitin-endoplasmic reticulum platform

AU - Zachari, Maria

AU - Gudmundsson, Sigurdur

AU - Li, Ziyue

AU - Manifava, Maria

AU - Shah, Ronak

AU - Smith, Matthew

AU - Stronge, James

AU - Karanasios, Eleftherios

AU - Piunti, Caterina

AU - Kishi-Itakura, Chieko

AU - Vihinen, Helena

AU - Jokitalo, Eija

AU - Guan, Jun-Lin

AU - Buss, Folma

AU - Smith, Andrew M.

AU - Walker, Simon A.

AU - Eskelinen, Eeva-Liisa

AU - Ktistakis, Nicholas T.

PY - 2019/7/15

Y1 - 2019/7/15

N2 - The dynamics and co-ordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes, or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to addressthese questions. Ubiquitination of mitochondrial fragments is required earliest followed by autophosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps whereas ULK1/2 are dispensable. Receptors act temporally and mechanistically upstream ofATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way suggesting multiple initiation events. Targeted ubiquitinated mitochondrial are cradled by endoplasmic reticulum strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands providing platforms for formation of the mitophagosomes.

AB - The dynamics and co-ordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes, or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to addressthese questions. Ubiquitination of mitochondrial fragments is required earliest followed by autophosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps whereas ULK1/2 are dispensable. Receptors act temporally and mechanistically upstream ofATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way suggesting multiple initiation events. Targeted ubiquitinated mitochondrial are cradled by endoplasmic reticulum strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands providing platforms for formation of the mitophagosomes.

KW - 1182 Biochemistry, cell and molecular biology

KW - autophagy

KW - mitophagy

KW - ivermectin

KW - ubiquitin

KW - endoplasmic reticulum

U2 - doi: 10.1016/j.devcel.2019.06.016

DO - doi: 10.1016/j.devcel.2019.06.016

M3 - Article

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

ER -