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An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia
Toshiro Saito, … , Mondira Kundu, Junichi Sadoshima
Toshiro Saito, … , Mondira Kundu, Junichi Sadoshima
Published December 4, 2018
Citation Information: J Clin Invest. 2019;129(2):802-819. https://doi.org/10.1172/JCI122035.
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Research Article Cardiology Cell biology Article has an altmetric score of 4

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

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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 trans-Golgi 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.

Authors

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

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Figure 9

Ulk1 directly phosphorylates Rab9 at S179, inducing mitochondrial fission and mitophagy.

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Ulk1 directly phosphorylates Rab9 at S179, inducing mitochondrial fissio...
(A) Phosphorylation of Rab9 in CMs was analyzed with Phos-tag SDS-PAGE. A band of approximately 20 kDa in all 4 lanes represents an unphosphorylated form of Rab9. In lanes 2 and 4, anti-Rab9 antibody recognized a band with a higher molecular weight representing a monophosphorylated form of Rab9. (B) Phosphorylation of YFP-Rab9 in CMs was analyzed with Phos-tag SDS-PAGE. Anti-Rab9 antibody detected 2 bands in lane 2. The lower band corresponds to an unphosphorylated form of YFP-Rab9. The upper band in lane 2 was abolished in lane 3, suggesting that S179 is the unique phosphorylation site in Rab9. (C) Co-IP assays. (D and E) Representative immunoblots are shown. In D, Rab9 was detected on a parallel gel using the same samples.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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