PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury

Autophagy. 2018;14(5):880-897. doi: 10.1080/15548627.2017.1405880. Epub 2018 Feb 17.

Abstract

Damaged or dysfunctional mitochondria are toxic to the cell by producing reactive oxygen species and releasing cell death factors. Therefore, timely removal of these organelles is critical to cellular homeostasis and viability. Mitophagy is the mechanism of selective degradation of mitochondria via autophagy. The significance of mitophagy in kidney diseases, including ischemic acute kidney injury (AKI), has yet to be established, and the involved pathway of mitophagy remains poorly understood. Here, we show that mitophagy is induced in renal proximal tubular cells in both in vitro and in vivo models of ischemic AKI. Mitophagy under these conditions is abrogated by Pink1 and Park2 deficiency, supporting a critical role of the PINK1-PARK2 pathway in tubular cell mitophagy. Moreover, ischemic AKI is aggravated in pink1 andpark2 single- as well as double-knockout mice. Mechanistically, Pink1 and Park2 deficiency enhances mitochondrial damage, reactive oxygen species production, and inflammatory response. Taken together, these results indicate that PINK1-PARK2-mediated mitophagy plays an important role in mitochondrial quality control, tubular cell survival, and renal function during AKI.

Keywords: PARK2; PINK1; autophagy; mitochondria; mitophagy; renal ischemia-reperfusion.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis
  • Autophagosomes / metabolism
  • Autophagosomes / ultrastructure
  • Cell Line
  • Gene Silencing
  • Humans
  • Kidney / pathology*
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitophagy*
  • Protein Kinases / metabolism*
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Signal Transduction*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Adenosine Triphosphate
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase

Grants and funding

This work was supported by National Natural Science Foundation of China (NSFC) [grant number 81720108008]; HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [grant number 058831]; HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); [grant number 087843]; U.S. Department of Veterans Affairs (VA) [grant number 000319]; National Natural Science Foundation of China (NSFC) [grant number 81430017]; National Natural Science Foundation of China (NSFC) [grant number 81570622].