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Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys.
Autophagy. 2019 12; 15(12):2142-2162.A

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.Abbreviations: ACTB: actin, beta; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; BUN: blood urea nitrogen; CASP3: caspase 3; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; COX4I1: cytochrome c oxidase subunit 4I1; COX8: cytochrome c oxidase subunit 8; DAPI: 4',6-diamidino-2-phenylindole; DNM1L: dynamin 1 like; EGFP: enhanced green fluorescent protein; EM: electron microscopy; ER: endoplasmic reticulum; FC: floxed control; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; H-E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HSPD1: heat shock protein family D (Hsp60) member 1; IMMT/MIC60: inner membrane mitochondrial protein; IPC: ischemic preconditioning; I-R: ischemia-reperfusion; IRI: ischemia-reperfusion injury; JC-1: 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mito-QC: mito-quality control; mRFP: monomeric red fluorescent protein; NAC: N-acetylcysteine; PINK1: PTEN induced putative kinase 1; PPIB: peptidylprolyl isomerase B; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; RPTC: rat proximal tubular cells; SD: standard deviation; sIPC: simulated IPC; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

Authors+Show Affiliations

Department of Cellular Biology and Anatomy, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.Departments of Laboratory Medicine and Nephrology The Second Xiangya Hospital, Central South University, Changsha, China.Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, Scotland, UK.Division of Cardiology, Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.Department of Cellular Biology and Anatomy, Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA. Departments of Laboratory Medicine and Nephrology The Second Xiangya Hospital, Central South University, Changsha, China.

Pub Type(s)

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

Language

eng

PubMed ID

31066324

Citation

Livingston, Man J., et al. "Clearance of Damaged Mitochondria Via Mitophagy Is Important to the Protective Effect of Ischemic Preconditioning in Kidneys." Autophagy, vol. 15, no. 12, 2019, pp. 2142-2162.
Livingston MJ, Wang J, Zhou J, et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy. 2019;15(12):2142-2162.
Livingston, M. J., Wang, J., Zhou, J., Wu, G., Ganley, I. G., Hill, J. A., Yin, X. M., & Dong, Z. (2019). Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy, 15(12), 2142-2162. https://doi.org/10.1080/15548627.2019.1615822
Livingston MJ, et al. Clearance of Damaged Mitochondria Via Mitophagy Is Important to the Protective Effect of Ischemic Preconditioning in Kidneys. Autophagy. 2019;15(12):2142-2162. PubMed PMID: 31066324.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. AU - Livingston,Man J, AU - Wang,Jinghong, AU - Zhou,Jiliang, AU - Wu,Guangyu, AU - Ganley,Ian G, AU - Hill,Joseph A, AU - Yin,Xiao-Ming, AU - Dong,Zheng, Y1 - 2019/05/22/ PY - 2019/5/9/pubmed PY - 2020/7/14/medline PY - 2019/5/9/entrez KW - Acute kidney injury KW - autophagy KW - ischemic preconditioning KW - mitophagy KW - proximal tubule KW - renal ischemia-reperfusion SP - 2142 EP - 2162 JF - Autophagy JO - Autophagy VL - 15 IS - 12 N2 - 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.Abbreviations: ACTB: actin, beta; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; BUN: blood urea nitrogen; CASP3: caspase 3; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; COX4I1: cytochrome c oxidase subunit 4I1; COX8: cytochrome c oxidase subunit 8; DAPI: 4',6-diamidino-2-phenylindole; DNM1L: dynamin 1 like; EGFP: enhanced green fluorescent protein; EM: electron microscopy; ER: endoplasmic reticulum; FC: floxed control; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; H-E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HSPD1: heat shock protein family D (Hsp60) member 1; IMMT/MIC60: inner membrane mitochondrial protein; IPC: ischemic preconditioning; I-R: ischemia-reperfusion; IRI: ischemia-reperfusion injury; JC-1: 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mito-QC: mito-quality control; mRFP: monomeric red fluorescent protein; NAC: N-acetylcysteine; PINK1: PTEN induced putative kinase 1; PPIB: peptidylprolyl isomerase B; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; RPTC: rat proximal tubular cells; SD: standard deviation; sIPC: simulated IPC; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/31066324/Clearance_of_damaged_mitochondria_via_mitophagy_is_important_to_the_protective_effect_of_ischemic_preconditioning_in_kidneys_ DB - PRIME DP - Unbound Medicine ER -