TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA

doi:10.1038/s41556-024-01419-6

. 2024 Jun;26(6):878-891.

doi: 10.1038/s41556-024-01419-6. Epub 2024 May 23.

TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA

Hao Liu^#^{1

2

3

4}, Cien Zhen^#^{1

5}, Jianming Xie^#^{1

6}, Zhenhuan Luo^#^{7

8}, Lin Zeng^#^{1

9

10

11}, Guojun Zhao^#⁴, Shaohua Lu¹, Haixia Zhuang², Hualin Fan^{1

5}, Xia Li¹, Zhaojie Liu¹, Shiyin Lin¹, Huilin Jiang¹², Yuqian Chen¹, Jiahao Cheng^{1

13}, Zhiyu Cao^{2

14}, Keyu Dai¹, Jinhua Shi¹, Zhaohua Wang¹, Yongquan Hu¹, Tian Meng¹, Chuchu Zhou¹, Zhiyuan Han¹, Huansen Huang², Qinghua Zhou^{7

8}, Pengcheng He^{9

10

11

15}, Du Feng^{16

17

18

19

20}

Affiliations

¹ State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
² Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
³ Huaihe Hospital of Henan University, Kaifeng City, China.
⁴ The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.
⁵ Department of Biology, University of Padova, Padova, Italy.
⁶ Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
⁷ Department of Cardiology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
⁸ College of Life Science and Technology, Jinan University, Guangzhou, China.
⁹ Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
¹⁰ Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
¹¹ Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
¹² Emergency Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
¹³ Department of Clinical Medicine, Nanshan School, Guangzhou Medical University, Guangzhou, China.
¹⁴ The First Clinical Medical School, Guangzhou Medical University, Guangzhou, China.
¹⁵ Department of Cardiology, Heyuan People's Hospital, Heyuan, China.
¹⁶ State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.
¹⁷ Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.
¹⁸ The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China. fenglab@gzhmu.edu.cn.
¹⁹ Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.
²⁰ The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.

^# Contributed equally.

PMID: 38783142
DOI: 10.1038/s41556-024-01419-6

TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA

Hao Liu et al. Nat Cell Biol. 2024 Jun.

. 2024 Jun;26(6):878-891.

doi: 10.1038/s41556-024-01419-6. Epub 2024 May 23.

Authors

Affiliations

¹ State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
² Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
³ Huaihe Hospital of Henan University, Kaifeng City, China.
⁴ The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.
⁵ Department of Biology, University of Padova, Padova, Italy.
⁶ Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
⁷ Department of Cardiology, The First Affiliated Hospital, Jinan University, Guangzhou, China.
⁸ College of Life Science and Technology, Jinan University, Guangzhou, China.
⁹ Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
¹⁰ Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
¹¹ Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
¹² Emergency Department, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
¹³ Department of Clinical Medicine, Nanshan School, Guangzhou Medical University, Guangzhou, China.
¹⁴ The First Clinical Medical School, Guangzhou Medical University, Guangzhou, China.
¹⁵ Department of Cardiology, Heyuan People's Hospital, Heyuan, China.
¹⁶ State Key Laboratory of Respiratory Disease, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.
¹⁷ Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.
¹⁸ The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China. fenglab@gzhmu.edu.cn.
¹⁹ Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.
²⁰ The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, China. fenglab@gzhmu.edu.cn.

^# Contributed equally.

PMID: 38783142
DOI: 10.1038/s41556-024-01419-6

Abstract

When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

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References

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1. Newman, L. E. & Shadel, G. S. Mitochondrial DNA release in innate immune signaling. Annu. Rev. Biochem. 92, 299–332 (2023). - PubMed - DOI
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[1] Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012). - PubMed - PMC - DOI

[2] Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012). - PubMed - PMC - DOI

[3] Newman, L. E. & Shadel, G. S. Mitochondrial DNA release in innate immune signaling. Annu. Rev. Biochem. 92, 299–332 (2023). - PubMed - DOI

[4] Newman, L. E. & Shadel, G. S. Mitochondrial DNA release in innate immune signaling. Annu. Rev. Biochem. 92, 299–332 (2023). - PubMed - DOI

[5] Bonekamp, N. A. & Larsson, N. G. SnapShot: mitochondrial nucleoid. Cell 172, 388.e1 (2018). - DOI

[6] Bonekamp, N. A. & Larsson, N. G. SnapShot: mitochondrial nucleoid. Cell 172, 388.e1 (2018). - DOI

[7] Menger, K. E., Rodriguez-Luis, A., Chapman, J. & Nicholls, T. J. Controlling the topology of mammalian mitochondrial DNA. Open Biol. 11, 210168 (2021). - PubMed - PMC - DOI

[8] Menger, K. E., Rodriguez-Luis, A., Chapman, J. & Nicholls, T. J. Controlling the topology of mammalian mitochondrial DNA. Open Biol. 11, 210168 (2021). - PubMed - PMC - DOI

[9] Nicholls, T. J. & Gustafsson, C. M. Separating and segregating the human mitochondrial genome. Trends Biochem. Sci. 43, 869–881 (2018). - PubMed - DOI

[10] Nicholls, T. J. & Gustafsson, C. M. Separating and segregating the human mitochondrial genome. Trends Biochem. Sci. 43, 869–881 (2018). - PubMed - DOI

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TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA

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TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA

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Abstract

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