An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia

Toshiro Saito, Jihoon Nah, Shinichi Oka, Risa Mukai, Yoshiya Monden, Yasuhiro Maejima, Yoshiyuki Ikeda, Sebastiano Sciarretta, Tong Liu, Hong Li, Erdene Baljinnyam, Diego Fraidenraich, Luke Fritzky, Peiyong Zhai, Shizuko Ichinose, Mitsuaki Isobe, Chiao Po Hsu, Mondira Kundu, Junichi Sadoshima

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/ thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of transGolgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.

Original languageEnglish (US)
Pages (from-to)802-819
Number of pages18
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019

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Mitochondrial Degradation
Autophagy
Ischemia
Mitochondria
Dynamins
Myocardial Ischemia
Proteins
Dynamin I
Phosphorylation
Protein-Serine-Threonine Kinases
Maintenance
Membranes
Wounds and Injuries
Autophagy-Related Protein-1 Homolog

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Saito, Toshiro ; Nah, Jihoon ; Oka, Shinichi ; Mukai, Risa ; Monden, Yoshiya ; Maejima, Yasuhiro ; Ikeda, Yoshiyuki ; Sciarretta, Sebastiano ; Liu, Tong ; Li, Hong ; Baljinnyam, Erdene ; Fraidenraich, Diego ; Fritzky, Luke ; Zhai, Peiyong ; Ichinose, Shizuko ; Isobe, Mitsuaki ; Hsu, Chiao Po ; Kundu, Mondira ; Sadoshima, Junichi. / An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 802-819.
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abstract = "Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/ thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of transGolgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.",
author = "Toshiro Saito and Jihoon Nah and Shinichi Oka and Risa Mukai and Yoshiya Monden and Yasuhiro Maejima and Yoshiyuki Ikeda and Sebastiano Sciarretta and Tong Liu and Hong Li and Erdene Baljinnyam and Diego Fraidenraich and Luke Fritzky and Peiyong Zhai and Shizuko Ichinose and Mitsuaki Isobe and Hsu, {Chiao Po} and Mondira Kundu and Junichi Sadoshima",
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Saito, T, Nah, J, Oka, S, Mukai, R, Monden, Y, Maejima, Y, Ikeda, Y, Sciarretta, S, Liu, T, Li, H, Baljinnyam, E, Fraidenraich, D, Fritzky, L, Zhai, P, Ichinose, S, Isobe, M, Hsu, CP, Kundu, M & Sadoshima, J 2019, 'An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia', Journal of Clinical Investigation, vol. 129, no. 2, pp. 802-819. https://doi.org/10.1172/JCI122035

An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. / Saito, Toshiro; Nah, Jihoon; Oka, Shinichi; Mukai, Risa; Monden, Yoshiya; Maejima, Yasuhiro; Ikeda, Yoshiyuki; Sciarretta, Sebastiano; Liu, Tong; Li, Hong; Baljinnyam, Erdene; Fraidenraich, Diego; Fritzky, Luke; Zhai, Peiyong; Ichinose, Shizuko; Isobe, Mitsuaki; Hsu, Chiao Po; Kundu, Mondira; Sadoshima, Junichi.

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 802-819.

Research output: Contribution to journalArticle

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T1 - An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia

AU - Saito, Toshiro

AU - Nah, Jihoon

AU - Oka, Shinichi

AU - Mukai, Risa

AU - Monden, Yoshiya

AU - Maejima, Yasuhiro

AU - Ikeda, Yoshiyuki

AU - Sciarretta, Sebastiano

AU - Liu, Tong

AU - Li, Hong

AU - Baljinnyam, Erdene

AU - Fraidenraich, Diego

AU - Fritzky, Luke

AU - Zhai, Peiyong

AU - Ichinose, Shizuko

AU - Isobe, Mitsuaki

AU - Hsu, Chiao Po

AU - Kundu, Mondira

AU - Sadoshima, Junichi

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/ thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of transGolgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.

AB - Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/ thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of transGolgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.

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