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
  • 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. [email protected].
  • 7. Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA, USA. [email protected].
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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