2. Academic Validation
  3. Role of Succinate Dehydrogenase in Age-Related Th17 Inflammation

Role of Succinate Dehydrogenase in Age-Related Th17 Inflammation

  • Aging Cell. 2026 Apr;25(4):e70451. doi: 10.1111/acel.70451.
Evelyn Ocegueda 1,  Gabrielle Chase 2,  Michaella Niceforo 2,  Aida Javidan 3,  Lydia Gugliuzza 2,  Jingting Yu 4,  Rachel Y Kang 5 6,  Ava Lankowski 1,  Olivia Stefanik 1,  Kailey Leclerc 2,  Yolander Valentine 3,  Micah J Drummond 7,  Jude T Deeney 8,  Josephine S Modica-Napolitano 2,  Elizabeth A Proctor 5 6 9 10,  Hatice Hasturk 11,  Barbara S Nikolajczyk 3 12,  Leena P Bharath 1
Affiliations

Affiliations

  • 1 Department of Health Sciences and Nutrition, Merrimack College, North Andover, Massachusetts, USA.
  • 2 Department of Natural Sciences, Merrimack College, North Andover, Massachusetts, USA.
  • 3 Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
  • 4 Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological Studies, La Jolla, California, USA.
  • 5 Department of Neurosurgery, Penn State College of Medicine, Hershey, Pennsylvania, USA.
  • 6 Department of Neuroscience & Experimental Therapeutics, Penn State College of Medicine, Hershey, Pennsylvania, USA.
  • 7 Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah, USA.
  • 8 Department of Endocrinology, Diabetes, Nutrition & Weight Management, Boston University School of Medicine, Boston, Massachusetts, USA.
  • 9 Department of Biomedical Engineering, Penn State Neuroscience Institute, Pennsylvania State University, University Park, Pennsylvania, USA.
  • 10 Department of Engineering Science & Mechanics, Penn State Neuroscience Institute, Pennsylvania State University, University Park, Pennsylvania, USA.
  • 11 ADA Forsyth Institute, Somerville, Massachusetts, USA.
  • 12 Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky, USA.
PMID: 41874464 DOI: 10.1111/acel.70451
Abstract

Age-related cellular changes negatively impact CD4+ T cell function. Our prior work showed that mitochondrial complex II (Succinate Dehydrogenase [SDH]) expression was upregulated in T cells from older (O) adults (60-80 years old). T cells from older adults also produced higher amounts of cytokines generally considered proinflammatory, such as Th17 cytokines IL-17A/F and IL-21, and the Th-17-supportive cytokine IL-6, compared to T cells from younger (Y) adults (25-40 years old). The objective of our study is to evaluate whether hyperactivation of SDH is required for the induction of proinflammatory cytokines and the mechanistic link between SDH and Th17 cytokine production. CD4+ T cells were isolated from lean normoglycemic younger (avg: 31.58 years; BMI 21.14 kg/m2) and older (avg: 64.81 years; BMI 21.95 kg/m2) adults. SDH was pharmacologically and genetically modulated, and mitochondrial structure, function, metabolites, and cytokine production were quantified. SDH activation in T cells from older adults induced heightened oxidation of succinate, disrupted the fumarate-to-succinate ratio, stabilized HIF-1α, and promoted Th17 cytokines. Genetic and pharmacological inhibition of SDH in T cells from older adults lowered proinflammatory cytokine production, whereas exogenous addition of cell-permeable succinate induced SDH protein in T cells from younger adults and recapitulated the proinflammatory Th17 profile observed in T cells from older adults. These data establish a mechanistic link between SDH and Th17 inflammation.

Keywords

Aging; Complex II; Cytokines; Mitochondria; SDH; T cells; Th17 cytokines.

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