Ulk1/Rab9-mediated alternative mitophagy confers cardioprotection during energy stress
Rimpy Dhingra, … , Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum
Rimpy Dhingra, … , Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum
Published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):509-512. https://doi.org/10.1172/JCI125980.
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Commentary

Ulk1/Rab9-mediated alternative mitophagy confers cardioprotection during energy stress

Abstract

The heart relies on mitochondria-derived energy production for continuous contraction and relaxation; therefore, the maintenance of a pool of healthy mitochondria is essential for sustaining normal cardiac performance. Mitophagy serves as a critical process for maintaining mitochondrial quality control and involves the PTEN-induced kinase 1/Parkin (Pink1/Parkin) pathway and autophagosomes labeled with the autophagy proteins autophagy-related 7 (ATG) and light chain 3 (LC3). In this issue of the JCI, Saito and colleagues identify an alternative pathway for mitophagy that utilizes the serine/threonine protein kinase Unc-51–like kinase 1 (Ulk1) and the small GTPase Rab9 to clear damaged mitochondria independently of conventional autophagy proteins. Together, the results of this study reveal that Ulk1 phosphorylation of Rab9 at serine 179 is critical for alternative mitophagy and cardioprotection under energy stress conditions.

Authors

Rimpy Dhingra, Inna Rabinovich-Nikitin, Lorrie A. Kirshenbaum

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Figure 1

Ulk1 phosphorylation of Rab9 at serine 179 is essential for mitophagy and cardioprotection during energy stress.

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Ulk1 phosphorylation of Rab9 at serine 179 is essential for mitophagy an...
In this issue of the JCI, a study by Saito et al. provides molecular insight into an alternative mitophagy pathway activated in the heart under energy stress conditions (17). Energy stress provoked by glucose deprivation or hypoxia/ischemia activates AMPK, which then phosphorylates Ulk1. Ulk1 forms a complex with the Ras-related protein Rab9, which is associated with a Golgi-derived membrane. Ulk1 phosphorylates Rab9 at serine 179, and phosphorylated Rab9 then serves as a platform for the formation of a complex between Rip1 and Drp1. Rip1 phosphorylates Drp1 at serine 616 in a Ulk1- and Rab9-dependent manner. Mitochondria with phosphorylated Drp1 are recognized and sequestered by Rab9-associated membranes, followed by fusion with lysosomes and digestion. The Rip kinase inhibitor necrostain-1 (Nec1) inhibits energy stress–induced mitophagy.