STAT3 modulates CD4+ T mitochondrial dynamics and function in aging

  • Aging Cell. 2023 Nov;22(11):e13996. doi: 10.1111/acel.13996.
Emelia Zukowski  1 ,  Marco Sannella  1 ,  Jack Donato Rockhold  1 ,  Gabriella H Kalantar  2 ,  Jingting Yu  3 ,  Sara SantaCruz-Calvo  4  5 ,  Madison K Kuhn  6 ,  Nasun Hah  7 ,  Ling Ouyang  7 ,  Tzu-Wen Wang  7 ,  Lyanne Murphy  8 ,  Heather Marszalkowski  8 ,  Kaleigh Gibney  1 ,  Micah J Drummond  9 ,  Elizabeth A Proctor  6  10 ,  Hatice Hasturk  11 ,  Barbara S Nikolajczyk  4  5 ,  Leena P Bharath  1
Affiliations
  • 1. Department of Nutrition and Public Health, Merrimack College, North Andover, Massachusetts, USA.
  • 2. Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA.
  • 3. Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, California, USA.
  • 4. Departments of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • 5. Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky, USA.
  • 6. Departments of Neurosurgery, Pharmacology, and Biomedical Engineering and Center for Neural Engineering, Pennsylvania State University, Hershey, Pennsylvania, USA.
  • 7. Next Generation Sequencing Core, The Salk Institute for Biological Studies, La Jolla, California, USA.
  • 8. Department of Biology, Merrimack College, North Andover, Massachusetts, USA.
  • 9. Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah, USA.
  • 10. Department of Engineering Science & Mechanics, Pennsylvania State University, Hershey, Pennsylvania, USA.
  • 11. Forsyth Institute, Cambridge, Massachusetts, USA.
PMID: 37837188 DOI: 10.1111/acel.13996
Abstract

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 Inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-related cytokine profiles. Our data show the mechanistic link among mitoSTAT3, mitochondrial dynamics, function, and T-cell cytokine production.

Keywords
CD4+ T cells; Th17 cytokines; aging; cytokines; inflammaging; mitochondria; mitochondrial STAT3; naïve CD4+ T cells.
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