Negative feedback system to maintain cell ROS homeostasis: KEAP1-PGAM5 complex senses mitochondrially generated ROS to induce mitophagy

Autophagy. 2022 Sep;18(9):2249-2251. doi: 10.1080/15548627.2021.2024702. Epub 2022 Jan 28.

Abstract

If cellular reactive oxygen species (ROS) production surpasses the intracellular antioxidant capacity, thus altering the ROS homeostasis, the cell needs to eradicate faulty mitochondria responsible for these excessive ROS. We have shown that even moderate ROS production breaks the KEAP1-PGAM5 complex, inhibiting the proteasomal removal of PGAM5. This leads to an accumulation of PGAM5 interfering with PINK1 processing that sensitizes mitochondria to autophagic removal. We propose that such a negative feedback system maintains cell ROS homeostasis.

Keywords: Feedback; KEAP1; PGAM5; mitochondrial ros production; mitophagy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Comment

MeSH terms

  • Autophagy
  • Feedback
  • Homeostasis
  • Kelch-Like ECH-Associated Protein 1
  • Mitochondrial Proteins* / metabolism
  • Mitophagy*
  • NF-E2-Related Factor 2
  • Phosphoprotein Phosphatases / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • Kelch-Like ECH-Associated Protein 1
  • Mitochondrial Proteins
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • Phosphoprotein Phosphatases

Grants and funding

This work was supported by the Estonian Research Council [PRG400]; European Regional Development Fund [2014-2020.4.01.15-0012]; Chan Zuckerberg Initiative [2021-240154]; Estonian - French Research Program PARROT [42402TF].