Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys

Man J. Livingston, Jinghong Wang, Jiliang Zhou, Guangyu Wu, Ian Ganley, Joseph A. Hill, Xiao-Ming Yin, Zheng Dong (Lead / Corresponding author)

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Abstract

Ischemic preconditioning (IPC) affords tissue protection in organs including kidneys; however, the underlying mechanism remains unclear. Here we demonstrate an important role of macroautophagy/autophagy (especially mitophagy) in the protective effect of IPC in kidneys. IPC induced autophagy in renal tubular cells in mice and suppressed subsequent renal ischemia-reperfusion injury (IRI). The protective effect of IPC was abolished by pharmacological inhibitors of autophagy and by the ablation of Atg7 from kidney proximal tubules. Pretreatment with BECN1/Beclin1 peptide induced autophagy and protected against IRI. These results suggest the dependence of IPC protection on renal autophagy. During IPC, the mitophagy regulator PINK1 (PTEN induced putative kinase 1) was activated. Both IPC and BECN1 peptide enhanced mitolysosome formation during renal IRI in mitophagy reporter mice, suggesting that IPC may protect kidneys by activating mitophagy. We further established an in vitro model of IPC by inducing ‘chemical ischemia’ in kidney proximal tubular cells with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Brief treatment with CCCP protected against subsequent injury in these cells and the protective effect was abrogated by autophagy inhibition. In vitro IPC increased mitophagosome formation, enhanced the delivery of mitophagosomes to lysosomes, and promoted the clearance of damaged mitochondria during subsequent CCCP treatment. IPC also suppressed mitochondrial depolarization, improved ATP production, and inhibited the generation of reactive oxygen species. Knockdown of Pink1 suppressed mitophagy and reduced the cytoprotective effect of IPC. Together, these results suggest that autophagy, especially mitophagy, plays an important role in the protective effect of IPC.

Original languageEnglish
Pages (from-to)2142-2162
Number of pages21
JournalAutophagy
Volume15
Issue number12
Early online date8 May 2019
DOIs
Publication statusPublished - Dec 2019

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Keywords

  • Acute kidney injury
  • autophagy
  • ischemic preconditioning
  • mitophagy
  • proximal tubule
  • renal ischemia-reperfusion

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