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

J Clin Invest. 2019 Feb 1;129(2):802-819. doi: 10.1172/JCI122035. Epub 2019 Jan 22.

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.

Keywords: Autophagy; Cardiology; Cell Biology; Heart failure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / metabolism
  • Autophagosomes / pathology
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Dynamins / genetics
  • Dynamins / metabolism
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria, Heart* / genetics
  • Mitochondria, Heart* / metabolism
  • Mitochondria, Heart* / pathology
  • Mitophagy / genetics*
  • Myocardial Ischemia* / genetics
  • Myocardial Ischemia* / metabolism
  • Myocardial Ischemia* / pathology
  • Myocardial Ischemia* / prevention & control
  • Myocardium* / metabolism
  • Myocardium* / pathology
  • Phosphorylation / genetics
  • Signal Transduction / genetics*
  • rab GTP-Binding Proteins* / genetics
  • rab GTP-Binding Proteins* / metabolism

Substances

  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Autophagy-Related Protein-1 Homolog
  • Ulk1 protein, mouse
  • rab9 protein, mouse
  • rab GTP-Binding Proteins
  • Dnm1l protein, mouse
  • Dynamins