2. Academic Validation
  3. Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging

Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging

  • Nat Aging. 2023 Jun 5. doi: 10.1038/s43587-023-00436-8.
Philip V Seegren 1 2,  Logan R Harper 1,  Taylor K Downs 1 2,  Xiao-Yu Zhao 2 3,  Shivapriya B Viswanathan 1,  Marta E Stremska 2 3,  Rachel J Olson 1,  Joel Kennedy 1,  Sarah E Ewald 2 3,  Pankaj Kumar 4 5,  Bimal N Desai 6 7
Affiliations

Affiliations

  • 1 Pharmacology Department, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 2 Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 3 Microbiology, Immunology, and Cancer Biology Department, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 4 Biochemistry and Molecular Genetics Department, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 5 University of Virginia, Bioinformatics Core, Charlottesville, VA, USA.
  • 6 Pharmacology Department, University of Virginia School of Medicine, Charlottesville, VA, USA. bdesai@virginia.edu.
  • 7 Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA, USA. bdesai@virginia.edu.
PMID: 37277641 DOI: 10.1038/s43587-023-00436-8
Abstract

Mitochondrial dysfunction is linked to age-associated inflammation or inflammaging, but underlying mechanisms are not understood. Analyses of 700 human blood transcriptomes revealed clear signs of age-associated low-grade inflammation. Among changes in mitochondrial components, we found that the expression of mitochondrial calcium uniporter (MCU) and its regulatory subunit MICU1, genes central to mitochondrial CA2+ (mCa2+) signaling, correlated inversely with age. Indeed, mCa2+ uptake capacity of mouse macrophages decreased significantly with age. We show that in both human and mouse macrophages, reduced mCa2+ uptake amplifies cytosolic CA2+ oscillations and potentiates downstream nuclear factor kappa B activation, which is central to inflammation. Our findings pinpoint the mitochondrial calcium uniporter complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to systemic macrophage-mediated age-associated inflammation. The findings raise the exciting possibility that restoring mCa2+ uptake capacity in tissue-resident macrophages may decrease inflammaging of specific organs and alleviate age-associated conditions such as neurodegenerative and cardiometabolic diseases.

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