Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis

Niranjana Natarajan, Jonathan Florentin, Ebin Johny, Hanxi Xiao, Scott Patrick O’Neil, Liqun Lei, Jixing Shen, Lee Ohayon, Aaron R. Johnson, Krithika Rao, Xiaoyun Li, Yanwu Zhao, Yingze Zhang, Sina Tavakoli, Sruti Shiva, Jishnu Das and Partha Dutta ()
Additional contact information
Niranjana Natarajan: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Jonathan Florentin: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Ebin Johny: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Hanxi Xiao: University of Pittsburgh
Scott Patrick O’Neil: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Liqun Lei: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Jixing Shen: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Lee Ohayon: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Aaron R. Johnson: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Krithika Rao: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Xiaoyun Li: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Yanwu Zhao: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Yingze Zhang: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Sina Tavakoli: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Sruti Shiva: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center
Jishnu Das: University of Pittsburgh
Partha Dutta: University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe−/− mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-51780-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51780-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-51780-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().