Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission
FUN14 domain-containing protein 1 (Fundc1)-dependent mitophagy, mainly activated by ischemic/hypoxic preconditioning, benefits acute myocardial reperfusion injury and chronic metabolic syndrome via sustaining mitochondrial homeostasis. Mitochondrial fission plays a pathogenic role in ischemic acute...
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doaj-b53f9c8b9aef4d27a2f37ae534e58f9f2020-11-24T21:42:11ZengElsevierRedox Biology2213-23172020-02-0130Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fissionJin Wang0Pingjun Zhu1Ruibing Li2Jun Ren3Hao Zhou4Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, ChinaChinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, ChinaChinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, ChinaShanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA; Corresponding author. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA; Corresponding author. Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China.FUN14 domain-containing protein 1 (Fundc1)-dependent mitophagy, mainly activated by ischemic/hypoxic preconditioning, benefits acute myocardial reperfusion injury and chronic metabolic syndrome via sustaining mitochondrial homeostasis. Mitochondrial fission plays a pathogenic role in ischemic acute kidney injury (AKI) through perturbation of mitochondrial quality and activation of mitochondrial apoptosis. The aim of our study was to explore the role of Fundc1 mitophagy in ischemia preconditioning (IPC)-mediated renoprotection. Proximal tubule-specific Fundc1 knockout (Fundc1PTKO) mice were subjected to ischemia reperfusion injury (IRI) and IPC prior to assessment of renal function, mitophagy, mitochondrial quality control, and Drp1-related mitochondrial fission. Following exposure to IPC, Fundc1 mitophagy was activated through post-transcriptional phosphorylation at Ser17. Interestingly, IRI-mediated renal injury, inflammation, and tubule cell death were mitigated by IPC whereas proximal tubule-specific Fundc1 knockout (Fundc1PTKO) mice abolished IPC-offered renoprotection. Mechanistically, IRI-evoked mitochondrial damage was improved by IPC whereas Fundc1 deficiency provoked mitochondrial abnormality, manifested by impaired mitochondrial quality and hyperactivated Drp1-dependent mitochondrial fission. Interestingly, Fundc1 deficiency-associated mitochondrial dysfunction was reversed by pharmacological inhibition of mitochondrial fission. In vivo, Fundc1 deletion-caused renal injury, severe pro-inflammatory response, and tubule cell death could be nullified by way of knockout Drp1 on Fundc1PTKO background. Finally, we also revealed that IPC triggered Fundc1 mitophagy activation through UNC-51-like kinase 1 (Ulk1) and Ulk1 ablation interrupted IPC-mediated Fundc1 activation and thus attenuated IPC-induced renoprotection. Fundc1 mitophagy, primarily driven by IPC, confers resistance to AKI through reconciliation of mitochondrial fission, implicating the therapeutic potential of targeting mitochondrial homeostasis for AKI. Keywords: Fundc1, Mitophagy, Ulk1, IPC, AKI, Mitochondrial fission, Drp1http://www.sciencedirect.com/science/article/pii/S2213231719315101 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jin Wang Pingjun Zhu Ruibing Li Jun Ren Hao Zhou |
spellingShingle |
Jin Wang Pingjun Zhu Ruibing Li Jun Ren Hao Zhou Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission Redox Biology |
author_facet |
Jin Wang Pingjun Zhu Ruibing Li Jun Ren Hao Zhou |
author_sort |
Jin Wang |
title |
Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission |
title_short |
Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission |
title_full |
Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission |
title_fullStr |
Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission |
title_full_unstemmed |
Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission |
title_sort |
fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic aki via suppression of drp1-mediated mitochondrial fission |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2020-02-01 |
description |
FUN14 domain-containing protein 1 (Fundc1)-dependent mitophagy, mainly activated by ischemic/hypoxic preconditioning, benefits acute myocardial reperfusion injury and chronic metabolic syndrome via sustaining mitochondrial homeostasis. Mitochondrial fission plays a pathogenic role in ischemic acute kidney injury (AKI) through perturbation of mitochondrial quality and activation of mitochondrial apoptosis. The aim of our study was to explore the role of Fundc1 mitophagy in ischemia preconditioning (IPC)-mediated renoprotection. Proximal tubule-specific Fundc1 knockout (Fundc1PTKO) mice were subjected to ischemia reperfusion injury (IRI) and IPC prior to assessment of renal function, mitophagy, mitochondrial quality control, and Drp1-related mitochondrial fission. Following exposure to IPC, Fundc1 mitophagy was activated through post-transcriptional phosphorylation at Ser17. Interestingly, IRI-mediated renal injury, inflammation, and tubule cell death were mitigated by IPC whereas proximal tubule-specific Fundc1 knockout (Fundc1PTKO) mice abolished IPC-offered renoprotection. Mechanistically, IRI-evoked mitochondrial damage was improved by IPC whereas Fundc1 deficiency provoked mitochondrial abnormality, manifested by impaired mitochondrial quality and hyperactivated Drp1-dependent mitochondrial fission. Interestingly, Fundc1 deficiency-associated mitochondrial dysfunction was reversed by pharmacological inhibition of mitochondrial fission. In vivo, Fundc1 deletion-caused renal injury, severe pro-inflammatory response, and tubule cell death could be nullified by way of knockout Drp1 on Fundc1PTKO background. Finally, we also revealed that IPC triggered Fundc1 mitophagy activation through UNC-51-like kinase 1 (Ulk1) and Ulk1 ablation interrupted IPC-mediated Fundc1 activation and thus attenuated IPC-induced renoprotection. Fundc1 mitophagy, primarily driven by IPC, confers resistance to AKI through reconciliation of mitochondrial fission, implicating the therapeutic potential of targeting mitochondrial homeostasis for AKI. Keywords: Fundc1, Mitophagy, Ulk1, IPC, AKI, Mitochondrial fission, Drp1 |
url |
http://www.sciencedirect.com/science/article/pii/S2213231719315101 |
work_keys_str_mv |
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