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

Toshiro Saito; Jihoon Nah; Shin ichi 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

doi:10.1172/JCI122035

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

Toshiro Saito, Jihoon Nah, Shin ichi 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 journal › Article › peer-review

155 Scopus citations

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 language	English (US)
Pages (from-to)	802-819
Number of pages	18
Journal	Journal of Clinical Investigation
Volume	129
Issue number	2
DOIs	https://doi.org/10.1172/JCI122035
State	Published - Feb 1 2019

All Science Journal Classification (ASJC) codes

Medicine(all)

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10.1172/JCI122035

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Saito, T., Nah, J., Oka, S. I., 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, C. P., Kundu, M., & Sadoshima, J. (2019). An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. Journal of Clinical Investigation, 129(2), 802-819. https://doi.org/10.1172/JCI122035

@article{d9bb62b5968e4060bfd5db76c5ef1562,

title = "An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia",

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 Oka, {Shin ichi} 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",

note = "Funding Information: The authors thank Daniela Zablocki (Rutgers New Jersey Medical School) for critical reading of the manuscript. This work was supported in part by grants from the US Public Health Service (HL67724, HL91469, HL102738, HL112330, HL138720, and AG23039, to JS) and the Leducq Foundation Transatlantic Network of Excellence (15CBD04 to JS). TS was supported by a postdoctoral fellowship from the American Heart Association and a research fellowship from the Japan Heart Foundation/Bayer Yakuhin. Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Investigation.All right reserved.",

year = "2019",

month = feb,

day = "1",

doi = "10.1172/JCI122035",

language = "English (US)",

volume = "129",

pages = "802--819",

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Saito, T, Nah, J, Oka, SI, 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

TY - JOUR

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

AU - Saito, Toshiro

AU - Nah, Jihoon

AU - Oka, Shin ichi

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

N1 - Funding Information: The authors thank Daniela Zablocki (Rutgers New Jersey Medical School) for critical reading of the manuscript. This work was supported in part by grants from the US Public Health Service (HL67724, HL91469, HL102738, HL112330, HL138720, and AG23039, to JS) and the Leducq Foundation Transatlantic Network of Excellence (15CBD04 to JS). TS was supported by a postdoctoral fellowship from the American Heart Association and a research fellowship from the Japan Heart Foundation/Bayer Yakuhin. Publisher Copyright: © 2018 American Society for Clinical Investigation.All right reserved.

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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U2 - 10.1172/JCI122035

DO - 10.1172/JCI122035

M3 - Article

C2 - 30511961

AN - SCOPUS:85058458189

SN - 0021-9738

VL - 129

SP - 802

EP - 819

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 2

ER -

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

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