An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages

Cell Rep. 2018 Mar 6;22(10):2654-2666. doi: 10.1016/j.celrep.2018.02.051.

Abstract

ECSIT is a mitochondrial complex I (CI)-associated protein that has been shown to regulate the production of mitochondrial reactive oxygen species (mROS) following engagement of Toll-like receptors (TLRs). We have generated an Ecsit conditional knockout (CKO) mouse strain to study the in vivo role of ECSIT. ECSIT deletion results in profound alteration of macrophage metabolism, leading to a striking shift to reliance on glycolysis, complete disruption of CI activity, and loss of the CI holoenzyme and multiple subassemblies. An increase in constitutive mROS production in ECSIT-deleted macrophages prevents further TLR-induced mROS production. Surprisingly, ECSIT-deleted cells accumulate damaged mitochondria because of defective mitophagy. ECSIT associates with the mitophagy regulator PINK1 and exhibits Parkin-dependent ubiquitination. However, upon ECSIT deletion, we observed increased mitochondrial Parkin without the expected increase in mitophagy. Taken together, these results demonstrate a key role of ECSIT in CI function, mROS production, and mitophagy-dependent mitochondrial quality control.

Keywords: ROS; complex I; glycolytic switch; mROS; macrophages; mitophagy; oxidative stress.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Electron Transport Complex I / metabolism*
  • Energy Metabolism
  • Gene Deletion
  • Glycolysis
  • Macrophages / metabolism*
  • Membrane Potential, Mitochondrial
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mitophagy*
  • Oxidative Phosphorylation
  • Protein Binding
  • Protein Stability
  • Reactive Oxygen Species / metabolism
  • Substrate Specificity
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • ECSIT protein, mouse
  • Reactive Oxygen Species
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Electron Transport Complex I