Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation

Weizhe Zhong; Zhuqing Rao; Jian Xu; Yu Sun; Haoran Hu; Ping Wang; Yongxiang Xia; Xiongxiong Pan; Weiwei Tang; Ziyi Chen; Haoming Zhou; Xuehao Wang

doi:10.1111/acel.13622

journal article Open Access May 22, 2022

Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation

Weizhe Zhong Zhuqing Rao Jian Xu

Yu Sun

Haoran Hu

Ping Wang

Yongxiang Xia Xiongxiong Pan Weiwei Tang

Ziyi Chen

Haoming Zhou

Xuehao Wang

Aging Cell Vol. 21 No. 6 · Wiley

View at Publisher Save 10.1111/acel.13622

Abstract

AbstractMacrophage‐stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age‐related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia‐reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Aging promoted the cytosolic leakage of macrophage mtDNA and enhanced STING activation, which was abrogated upon mtDNA depletion or cyclic GMP‐AMP Synthase (cGAS) inhibition. Aged macrophages exhibited increased mitochondrial injury with impaired mitophagy. Mechanistically, a decline in the PTEN‐induced kinase 1 (PINK1)/Parkin‐mediated polyubiquitination of mitochondria was observed in aged macrophages. Pink1 overexpression reversed the inhibition of mitochondrial ubiquitination but failed to promote mitolysosome formation in the aged macrophages. Meanwhile, aging impaired lysosomal biogenesis and function in macrophages by modulating the mTOR/transcription factor EB (TFEB) signaling pathway, which could be reversed by Torin‐1 treatment. Consequently, Pink1 overexpression in combination with Torin‐1 treatment restored mitophagic flux and inhibited mtDNA/cGAS/STING activation in aged macrophages. Moreover, besides HR‐induced metabolic stress, other types of oxidative and hepatotoxic stresses inhibited mitophagy and promoted the cytosolic release of mtDNA to activate STING signaling in aged macrophages. STING deficiency protected aged mice against diverse types of sterile inflammatory liver injuries. Our findings suggest that aging impairs mitophagic flux to facilitate the leakage of macrophage mtDNA into the cytosol and promotes STING activation, and thereby provides a novel potential therapeutic target for sterile inflammatory liver injury in aged patients.

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References

Details

Published: May 22, 2022
Vol/Issue: 21(6)
License: View

Authors

W

Weizhe Zhong

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

Z

Zhuqing Rao

Department of Anesthesiology The First Affiliated Hospital with Nanjing Medical University Nanjing China

J

Jian Xu

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

Y

Yu Sun

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

H

Haoran Hu

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

P

Ping Wang

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

Y

Yongxiang Xia

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

X

Xiongxiong Pan

Department of Anesthesiology The First Affiliated Hospital with Nanjing Medical University Nanjing China

W

Weiwei Tang

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

Z

Ziyi Chen

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

H

Haoming Zhou

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

X

Xuehao Wang

Hepatobiliary/Liver Transplantation Center The First Affiliated Hospital of Nanjing Medical University Nanjing China; Key Laboratory of Liver Transplantation Chinese Academy of Medical Sciences Nanjing China; NHC Key Laboratory of Living Donor Liver Transplantation Nanjing Medical University Nanjing China

Funding

National Natural Science Foundation of China Award: 81470901

Natural Science Foundation of Jiangsu Province Award: BK20191490

Six Talent Peaks Project in Jiangsu Province Award: 2018‐WSN‐011

Cite This Article

Weizhe Zhong, Zhuqing Rao, Jian Xu, et al. (2022). Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation. Aging Cell, 21(6). https://doi.org/10.1111/acel.13622

Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation

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